Tri-halo prostaglandin intermediates

ABSTRACT

Prostaglandin E (PGE)-type derivatives and analogs having a 6-keto feature are disclosed, including processes for preparing them and the appropriate intermediates, said derivatives having pharmacological activity. 
     A typical 6-keto compound is 6-keto-PGE 1 , methyl ester, represented by the formula: ##STR1##

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 829,678, filed Sept. 3, 1977,which is a continuation-in-part of copending application Ser. No.755,674 filed Dec. 30, 1976, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to prostaglandin derivatives and to a process forpreparing them.

The prostaglandins and analogs are well-known organic compounds derivedfrom prostanoic acid which has the following structure and atomnumbering: ##STR2##

As drawn hereinafter the formulas represent a particular opticallyactive isomer having the same absolute configuration as PGE₁ obtainedfrom mammalian tissues.

In the formulas, broken line attachments to the cyclopentane ring orside chain indicate substituents in alpha configuration, i.e. below theplane of the ring or side chain. Heavy solid line attachments indicatesubstituents in beta configuration, i.e. above the plane.

SUMMARY OF THE INVENTION

It is the purpose of this invention to provide novel products havingpharmacological activity. It is a further purpose to provide a processfor preparing these products and their intermediates.

Accordingly, there is provided an optically active compound of theformula ##STR3## or a mixture comprising that compound and theenantiomer thereof, including the lower alkanoates.

In formula I and in other formulas hereinafter including formulas in theCharts, the terms D, L, Q, R₁, and the like are as defined in the TABLE.Reference to that Table will establish what is intended to berepresented by each formula.

In formula I as used herein, attachment to R₁₈ corresponds to bonds tothe cyclopentane ring at the C-8, C-9, and C-12 positions followingprostaglandin nomenclature, thus ##STR4## and, similarly, in formulasIII and IV ##STR5##

TABLE DEFINITION OF TERMS FOR FORMULAS

D is

(1) --(CH₂)_(d) --C(R₂)₂ --

(2) --ch₂ --o--ch₂ --y-- or

(3) --CH₂ CH═CH--

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being thesame or different with the proviso that one R₂ is not methyl when theother is fluoro, and Y is a valence bond, --CH₂ --, or --(CH₂)₂ --.

D₁ is the same as D above but without --CH₂ CH═CH--.

L₁ is ##STR6## or a mixture of ##STR7## wherein R₃₄ and R₃₅ arehydrogen, methyl, or fluoro, being the same or different, with theproviso that one of R₃₄ and R₃₅ is fluoro only when the other ishydrogen or fluoro;

L₂ and L₃ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or--COOR₃₂, wherein R₃₂ is hydrogen, alkyl of one to 12 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenyl substituted one, 2, or3 chloro or alkyl of one to 3 carbon atoms, inclusive; being the same ordifferent, with the proviso that not more than one of L₂ and L₃ is--COOR₃₂.

M₁ is ##STR8## wherein R₃₃ is hydrogen or methyl.

Q is ##STR9## wherein R₈ is hydrogen, methyl, or ethyl.

Q₁ is ##STR10## wherein R₈ is hydrogen, methyl, or ethyl, and R₂₁ istetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, or a group of theformula ##STR11## wherein R₁₄ is alkyl of one to 18 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one,2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₁₅ and R₁₆are the same or different, being hydrogen, alkyl of one to 4 carbonatoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkylof one to 4 carbon atoms, inclusive, or, when R₁₅ and R₁₆ are takentogether, --(CH₂)₂ --or --(CH₂)_(b) --O--(CH₂)_(c) -- wherein a is 3, 4,or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that bplus c is 2, 3, or 4, and wherein R₁₇ is hydrogen or phenyl.

Q₂ is ##STR12##

Q₃ is ##STR13## wherein R₂₁ is as defined for Q₁ above.

R₁ is ##STR14## wherein R₃ is (a) hydrogen, (b) alkyl of one to 12carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms,inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl,(f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4carbon atoms, inclusive, ##STR15## wherein R₁₀ is phenyl, p-bromophenyl,p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, andwherein R₁₁ is hydrogen or benzoyl, or (n) a pharmacologicallyacceptable cation, wherein R₉ is hydrogen, methyl, or ethyl, and R₂₈ ishydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of oneto 4 carbon atoms, inclusive.

R₂ is hydrogen, methyl, or fluoro, being the same or different with theproviso that one R₂ is not methyl when the other is fluoro.

R₃ is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c)cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2,or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR16##wherein R₁₀ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl,p-benzamidophenyl, or 2-naphthyl, and wherein R₁₁ is hydrogen orbenzoyl, or (n) a pharmacologically acceptable cation.

R₄ is ##STR17## wherein C_(g) H_(2g) is alkylene of one to 9 carbonatoms, inclusive, with one to 5 carbon atoms, inclusive, in the chainbetween --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen,alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same ordifferent, with the proviso that one of R₅ and R₆ is fluoro only whenthe other is hydrogen or fluoro and the further proviso that neither R₅nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom(--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond oralkylene of one to 9 carbon atoms, inclusive, with one to 6 carbonatoms, inclusive, in the chain between CR₅ R₆ -- and the phenyl ring;

wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or alkoxy of one to 4 carbon atoms, inclusive, and s iszero, one, 2 or 3, with the proviso that not more than two T's are otherthan alkyl and when s is 2 or 3 the T's are either the same ordifferent.

R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, orfluoro, being the same or different, with the proviso that one of R₅ andR₆ is fluoro only when the other is hydrogen or fluoro and the furtherproviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--). R₇ is##STR18## wherein C-9 is attached to ##STR19##

R₈ is hydrogen, methyl, or ethyl.

R₉ is hydrogen, methyl, or ethyl.

R₁₀ is phenyl, p-bromophenyl, p-phenylyl, p-nitrophenyl,p-benzamidophenyl, or 2-naphthyl.

R₁₁ is hydrogen or benzoyl.

R₁₄ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive,phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbonatoms, inclusive.

R₁₅ and R₁₆ are the same or different, being hydrogen, alkyl of one to 4carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3alkyl of one to 4 carbon atoms, inclusive, or, when R₁₅ and R₁₅ aretaken together --(CH₂)_(a) -- or --(CH₂)_(b) --O--(CH₂)_(c) -- wherein ais 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the provisothat b plus c is 2, 3, or 4.

R₁₇ is hydrogen or phenyl.

R₁₈ is ##STR20## wherein C-9 is attached to ##STR21##

R₁₉ is ##STR22## wherein R₂₀ is the same as R₃ above except that it doesnot include "(n) a pharmacologically acceptable cation", and R₉ and R₂₈are as defined herein.

R₂₀ is the same as R₃ above except that it does not include "(n) apharmacologically acceptable cation".

R₂₁ is tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, or a groupof the formula ##STR23## wherein R₁₄ is alkyl of one to 18 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one,2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₁₅ and R₁₆are the same or different, being hydrogen, alkyl of one to 4 carbonatoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkylof one to 4 carbon atoms, inclusive, or, when R₁₅ and R₁₆ are takentogether, --(CH₂)_(a) --or --(CH₂)_(b) --O--(CH₂)_(c) -- wherein a is 3,4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso thatb plus c is 2, 3, or 4, and wherein R₁₇ is hydrogen or phenyl.

R₂₂ is ##STR24## wherein R₂₁ is as defined above and wherein C-9 isattached to ##STR25##

R₂₃ is ##STR26## wherein R₉, R₂₀, R₂₁ and R₂₈ are as defined herein.

R₂₈ is ##STR27## wherein C_(g) H_(2g) is alkylene of one to 9 carbonatoms, inclusive, with one to 5 carbon atoms, inclusive, in the chainbetween --CR₅ R₆ --and terminal methyl, wherein R₅ and R₆ are hydrogen,alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same ordifferent, with the proviso that one of R₅ and R₆ is fluoro only whenthe other is hydrogen or fluoro and the further proviso that neither R₅nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom(--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond oralkylene of one to 9 carbon atoms, inclusive, with one to 6 carbonatoms, inclusive between CR₅ R₆ --and the phenyl ring; wherein T isalkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or alkoxy of one to 4 carbon atoms, inclusive, and s iszero, one, 2 or 3, with the proviso that not more than two T's are otherthan alkyl and when s is 2 or 3 the T's are either the same ordifferent.

R₂₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkylof one to 4 carbon atoms, inclusive.

R₂₃ is bromo or chloro.

R₃₀ is ##STR28## wherein m is one to 5, inclusive, T is chloro, fluoro,trifluoromethyl, alkyl of one to 4 carbon atoms, inclusive, or alkoxy ofone to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, thevarious T's being the same or different, with the proviso that not morethan two T's are other than alkyl, with the further proviso that R₃₀ is##STR29## wherein T and s are as defined above, only when R₃₄ and R₃₅ asdefined above for L₁ are hydrogen or methyl, being the same ordifferent.

R₃₁ is hydrogen or hydroxy.

R₃₂ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkylof 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms,inclusive, phenyl, or phenyl substituted with one, 2, or 3 chloro oralkyl of one to 4 carbon atoms, inclusive.

R₃₃ is hydrogen or methyl.

R₃₄ and R₃₅ are hydrogen, methyl or fluoro, being the same or different,with the proviso that one of R₃₄ and R₃₅ is fluoro only when the otheris hydrogen or fluoro.

R₃₆ is ##STR30## wherein R₂₁ is as defined above and wherein C-9 isattached to ##STR31##

R₃₇ is iodo, bromo, or chloro.

T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or alkoxy of one to 4 carbon atoms, inclusive, with theproviso that not more than two T's are other than alkyl and when s is 2or 3 the T's are either the same or different.

V₁ is

(1) cis-CH═CH--CH₂ --(CH₂)_(p) --CH₂ --,

(2) cis-CH═CH--CH₂ --(CH₂)_(p) --CF₂ --,

(3) cis--CH═CH--D--

wherein D is as defined above and p is one, 2, or 3.

X is

(1) trans-CH═CH--

(2) cis-CH═CH--

(3) --c.tbd.c-- or

(4) --CH₂ CH₂ --.

X₁ is

(1) trans-CH═CH--

(2) --c.tbd.c-- or

(3) --CH₂ CH₂ --.

Y is a valence bond, --CH₂ --or --(CH₂)₂ --.

z is an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is avalence bond or alkylene of one to 9 carbon atoms, inclusive, with oneto 6 carbon atoms, inclusive in the chain between CR₅ R₆ --and thephenyl ring.

a is 3, 4, or 5.

b is one, 2, or 3.

c is one, 2, or 3.

d is zero to 5, inclusive.

f is zero to 4.

m is one to 5, inclusive.

p is one, 2, or 3.

s is zero, one, 2, or 3.

C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with oneto 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ --andterminal methyl.

C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms,inclusive, with one to 6 carbon atoms, inclusive, in the chain between--CR₅ R₆ --and the phenyl ring.

Within the scope of the prostaglandin derivatives described herein thereare represented

(a) PGE compounds when ##STR32## is ##STR33##

(b) 11β-PGE compounds when ##STR34## is ##STR35##

(c) 11-Deoxy-PGE compounds when ##STR36## is ##STR37##

(d) 11-Deoxy-11-methylene-PGE compounds when ##STR38## is ##STR39## and

(e) 11-Deoxy-11-hydroxymethyl-PGE compounds when ##STR40## is ##STR41##

Further within the scope of the prostaglandin derivatives describedherein there are represented

(a) PGE-type acids, esters and salts when R₁ is --COOR₃,

(b) 2-Decarboxy-2-hydroxymethyl-PGE type compounds when R₁ is --CH₂ OH,

(c) 2-Decarboxy-2-amino-PGE type compounds when R₁ is --CH₂ N(R₉)(R₂₈),

(d) PGE-type amides when R₁ is ##STR42## and

(e) 2-Decarboxy-2-tetrazol-1yl-PGE type compounds when R₁ is ##STR43##

For those compounds of formula I wherein O is ##STR44## i.e. wherein theC-15 hydroxyl group is attached to the siJe chain in alphaconfiguration, the configuration at C-15 is identical with that of thenaturally occuring prostaglandis such as PGE₁ obtained from mammaliantissues. The 15-epimer compounds are represented by formula I when Q is##STR45## and are identified variously as "15-epi" or "15β" or "15R" bythe appropriate prefix in the name. As is known in the art, "R" and "S"designations depend on the neighboring substituents. See R. S. Cahn, J.Chem. Ed. 41, 116 (1964).

A typical example of the compounds of formula I is represented by theformula ##STR46## and named 6-keto-PGE₁, methyl ester. The formula-IIcompound is a species of the formula-I compounds wherein D is --(CH₂)₃--, Q is ##STR47## R₁ is COOCH₃, R₄ is n-pentyl, ##STR48## is ##STR49##and X is trans-CH═CH--.

Regardless of the number of carbon atoms in the chain between the ketogroup and the terminal R₁ group, these compounds are regarded as"6-keto" compounds, from the designation of C-6 in the basic PGE₁formula referring back to the prostanoic acid skeleton. Compounds havinglonger or shorter chains are named following the accepted conventionsusing "homo" or "nor". For example the side chain ##STR50## is named "2a-homo-6-keto...", whereas ##STR51## is named "2-nor-6-keto...".

The products of this invention within the scope of formula I areextremely potent in causing various biological responses. For thatreason, these compounds are useful for pharmacological purposes. A fewof those biological responses are: inhibition of blood plateletaggregation, stimulation of smooth muscle, systemic blood pressurelowering, inhibiting gastric secretion and reducing undesirablegastrointestinal effects from systemic administration of prostaglandinsynthetase inhibitors, controlling spasm and facilitating breathing inasthmatic conditions, decongesting nasal passages, affecting thereproductive organs of mammals as labor inducers, abortifacients,cervical dilators, regulators of the estrus, and regulators of themenstrual cycle, accelerating growth of epidermal cells and keratin inanimals, and alleviating the symptoms of proliferating skin diseases.

Because of these biological responses, these novel compounds are usefulto study, prevent, control, or alleviate a wide variety of diseases andundesirable physiological conditions in mammals, including humans,useful domestic animals, pets, and zoological specimens, and inlaboratory animals, for example, mice, rats, rabbits, and monkeys.

These compounds are useful whenever it is desired to inhibit plateletaggregation, to reduce the adhesive character of platelets, and toremove or prevent the formation of thrombi in mammals, including man,rabbits, and rats. For example, these compounds are useful in thetreatment and prevention of myocardial infarcts, to treat and preventpost-operative thrombosis, to promote patency of vascular graftsfollowing surgery, and to treat conditions such as atherosclerosis,arteriosclerosis, blood clotting defects due to lipemia, and otherclinical conditions in which the underlying etiology is associated withlipid imbalance or hyperlipidemia. Other in vivo applications includegeriatric patients to prevent cerebral ischemic attacks and long termprophylaxis following myocardial infarcts and strokes. For thesepurposes, these compounds are administered systemically, e.g.intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.01 to about 10 mg. per kg. of bodyweight per day are used, the exact dose depending on the age, weight,and condition of the patient or animal, and on the frequency and routeof administration.

The addition of these compounds to whole blood provides in vitroapplications such as, storage of whole blood to be used in heart-lungmachines. Additionally whole blood containing these compounds can becirculated through organs, e.g. heart and kidneys, which have beenremoved from a donor prior to transplant. They are also useful inpreparing platelet rich concentrates for use in treatingthrombocytopenia, chemotherapy, and radiation therapy. In vitroapplications utilize a dose of 0.0001-1.0 μg/ml of whole blood.

These compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, they are useful in place of or in combination with less thanusual amounts of these known smooth muscle stimulators, for example, torelieve the symptoms of paralytic ileus, or to control or prevent atonicuterine bleeding after aborting or delivery, to aid in expulsion of theplacenta, and during the puerperium. For the latter purpose, thecompound is administered by intravenous infusion immediately afterabortion or delivery at a dose in the range about 0.01 to about 50 μg.per kg. of body weight per minute until the desired effect is obtained.Subsequent doses are given by intravenous, subcutaneous, orintramuscular injection or infusion during puerperium in the range 0.01to 2 mg. per kg. of body weight per day, the exact dose depending on theage, weight, and condition of the patient or animal.

These compounds are useful as hypotensive agents to reduce bloodpressure in mammals, including man. For this purpose, the compounds areadministered by intravenous infusion at the rate about 0.01 to about 50μg. per kg. of body weight per minute or in single or multiple doses ofabout 25 to 500 μg. per kg. of body weight total per day.

These prostaglandin derivatives are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reduce or avoid gastrointestinalulcer formation and accelerate the healing of such ulcers alreadypresent in the gastrointestinal tract. For this purpose, these compoundsare injected or infused intravenously subcutaneously, or intramuscularlyin an infusion dose range about 0.1 μg. to about 20 μg. per kg. of bodyweight per minute, to in a total daily dosage by injection or infusionin the range about 0.01 to about 10 mg. per kg. of body weight per day,the exact dose depending on the age, weight, and condition of thepatient or animal, and on the frequency and route of administration.

These compounds are also useful in reducing the undesirablegastrointestinal effects resulting from systemic administration ofanti-inflammatory prostaglandin synthetase inhibitors, and are used forthat purpose by concimtant aministration of the prostaglandin derivativeand the anti-inflammatory prostaglandin synthetase inhibitor. SeePartridge et al., U.S. Pat. No. 3,781,429, for a disclosure that theulcergenic effect induced by certain non-steroidal anti-inflammatoryagents in rats is inhibited by concomitant oral administration ofcertain prostaglandins of the E and A series, including PGE₁, PGE₂,PGE₃, 13,14-dihydro-PGE₁, and the corresponding 11-deoxy-PGE and PGAcompounds. Prostaglandins are useful, for example, in reducing theundesirable gastrointestinal effects resulting from systemicadministration of indomethacin, phenylbutazone, and aspirin. Thesesubstances specifically mentioned in Partridge et al. as non-steroidal,anti-inflammatory agents. These are also known to be prostaglandinsynthetase inhibitors. The anti-inflammatory synthetase inhibitor, forexample, indomethacin, aspirin, or phenylbutanzone is administered inany of the ways known in the art to alleviate an inflammatory condition,for example, in any dosage regimen and by any of the known routes ofsystemic administration.

The prostaglandin derivative is administered along with theanti-inflammatory prostaglandin synthetase inhibitor either by the sameroute of administration or by a different route. For example, if theanti-inflammatory substance is being administered orally, theprostaglandin derivative is also administered orally, or, alternatively,is administered rectally in the form of a suppository or, in the case ofwomen, vaginally in the form of a suppository or a vaginal device forslow release, for example as described in U.S. Pat. No. 3,545,439.Alternatively, if the anti-inflammatory substance is being administeredrectally, the prostaglandin derivative is also administered rectally.Further, the prostaglandin derivative can be conveniently administeredorally or, in the case of women, vaginally. It is especially convenientwhen the administration route is to be the same for bothanti-inflammatory substance and prostaglandin derivative, to combineboth into a single dosage form.

The dosage regimn for the prostaglandin derivative in accord with thistreatment will depend upon a variety of factors, including the type,age, weight, sex and medical conditon of the mammal, the nature anddosage regimen of the anti-inflammatory synthetase inhibitor beingadministered to the mammal, the sensitivity of the particularprostaglandin derivative to be administered. For example, not everyhuman in need of an anti-inflammatory substance experiences the sameadverse gastrointestinal effects when taking the substance. Thegastrointestinal effects will frequently vary substantially in kind anddegree. But it is within the skill of the attending physician orveterinarian to determine that administration of the antii-inflammatorysubstance is causing undesirable gastrointestinal effects in the humanor animal subject and to prescribe an effective amount of theprostaglandin derivative to reduce and then substantially to eliminatethose undesirable effects.

These compounds are also useful in the treatment of asthma. For example,these compounds are useful as bronchodilators or as inhibitors ormediators, such as SRS-A, and histamine which are released from cellsactivated by an antigen-antibody complex. Thus, these compounds controlspasm and facilitate breathing in conditions such as bronchial asthma,bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes,these compounds are administered in a variety of dosage forms, e.g.,orally in the form of tablets, capsules, or liquids; rectally in theform of suppositories; parenterally, subcutaneously, or intramuscularly,with intravenous administration being preferred in emergency situations;by inhalation in the form of aerosols or solutions for nebulizers; or byinsufflation in the form of powder. Doses in the range of about 0.01 to5 mg. per kg. of body weight are used 1 to 4 times a day, the exact dosedepending on the age, weight, and condition of the patient and on thefrequency and route of administration. For the above use theseprostaglandins can be combined advantageously with other anti-asthmaticagents, such as sympathomimetics (isoproterenol, phenylephrine,ephedrine, etc.); xanthine derivatives (theophylline and aminophylline);and corticosteroids (ACTH and prednisolone).

These compounds are efffectively administered to human asthma patientsby oral inhalation or by aerosol inhalation.

For administration by the oral inhalation route with conventionalnebulizers or by oxygen aerosolization it is convenient to provide theinstant active ingredient in dilute solution, preferably atconcentration of about 1 part of medicament to form about 100 to 200parts by weight of total solution. Entirely conventional additives maybe employed to stabilize these solutions or to provide isotonic media,for example, sodium chloride, sodium citrate, citric acid, sodiumbissulfide, and the like can be employed.

For administration as a self-propelled dosage unit for administering theactive ingredient in aerosol form suitable for inhalation therapy thecomposition can comprise the active ingredient suspended in an inertpropellant (such as a mixture of dichlorodifluoromethane anddichlorotetrafluoroethane) together with a co-solvent, such as ethanol,flavoring materials and stabilizers. Instead of a co-solvent there canalso be used a dispensing agent such as oleyl alcohol. Suitable means toemploy the aerosol inhalation therapy technique are described fully inU.S. Pat. No. 2,868,691 for example.

These compounds are useful in mammals, including man, as nasaldecongestants and are used for this purpose in a dose range of about 10μg. to about 10 mg. per ml. of a pharmacologically suitable liquidvehicle or as an aerosol spray, both for topical application.

These compounds are also useful in treating peripheral vascular diseasein humans. The term peripheral vascular disease as used herein meansdisease of any of the blood vessels outside of the heart and to diseaseof the lymph vessels, for example, frostbite, ischemic cerebrovasculardisease, artheriovenous fistulas, ischemic leg ulcers, phlebitis, venousinsufficiency, gangrene, hepatorenal syndrome, ductus arteriosus,non-obstructive mesenteric ischemia, arteritis lymphangitis and thelike. These examples are included to be illustrative and should not beconstrued as limiting the term peripheral vascular disease. For theseconditions the compounds of this invention are administered orally orparenterally via injection or infusion directly into a vein or artery,intra-venous or intra-arterial injections being preferred. The dosagesof these compounds are in the range of 0.01-1.0 μg. administered byinfusions at an hourly rate or by injection on a daily basis, i.e. 1-4times a day, the exact dose depending on the age, weight, and conditionof the patient and on the frequency and route of administration.Treatment is continued for one to five days, although three days isordinarily sufficient to assure long-lasting therapeutic action. In theevent that systemic or side effects are observed the dosage is loweredbelow the threshold at which such systemic or side effects are observed.

These compounds are accordingly useful for treating peripheral vasculardiseases in the extremities of humans who have circulatoryinsufficiencies in said extremities, such treatment affording relief ofrest pain and induction of heaing of ulcers. For complete discussion ofthe nature of and clinical manifestations of human peripheral vasculardisease and the method previously known of its treatment withprostaglandins see South African Pat. No. 74/0149 referenced as DerwentFarmdoc No. 58,400V. See Elliott, et al, Lancet, Jan. 18, 1975, pp.140-142.

These compounds which are useful in place of oxytocin to induce laborare used in pregnant female animals, including man, cows, sheep, andpigs, at or near term, or in pregnant animals with intrauterine death ofthe fetus from about 20 weeks to term. For this purpose, the compound isinfused intravenously at a dose of 0.01 to 50 μg. per kg. of body weightper minute until or near the termination of the second stage of labor,i.e. expulsion of the fetus. These compounds are especially useful whenthe female is one or more weeks post-mature and natural labor as notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started. An alternative route of administration isoral.

These compounds are further useful for controlling the reproductivecycle in menstruating female mammals, including humans. By the termmenstruating female mammals is meant animals which are mature enough tomenstruate, but not so old that regular menstruation has ceased. Forthat purpose the prostaglandin derivative is administered systemicallyat a dose level in the range 0.01 mg. to about 20 mg. per kg. of bodyweight of the female mammal, advantageously during a span of timestarting approximately at the time of ovulation and ending approximatelyat the time of menses or just prior to menses. Intravaginal andintrauterine routes are alternate methods of administration.Additionally, explusion of an embryo or a fetus is accomplished bysimilar administration of the compound during the first or secondtrimester of the normal mammalian gestation period.

These compounds are further useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by these compounds is useful inassisting sperm movement to the uterus. Cervical dilation byprostaglandins is also usefu in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause perforation of the uterus, cervical tears, or infections. It isalso useful in diagnostic procedures where dilation is necessary fortissue examination. For these purposes, the prostaglandin derivative isadministered locally or systemically.

The prostaglandin derivative, for example, is administered orally orvaginally at doses of about 5 to 50 mg. per treatment of an adult femalehuman, with from one to five treatments per 24 hour period.Alternatively the compound is administered intramuscularly orsubcutaneously at doses of about one to 25 mg. per treatment. The exactdosages for these purposes depend on the age, weight, and conditon ofthe patient or animal.

these compounds are further useful in domestic animals as anabortifacient (especiay for feedlot heifers), as an aid to estrusdetection, and for regulation or synchronization of estrus. Domesticanimals include horses, cattle, sheep, and swine. The regulation orsynchronization of estrus allows for more efficient management of bothconception and labor by enabling the herdsman to breed all his femalesin short pre-defined intervals. This synchronization results in a higherpercentage of live births than the percentage achieved by naturalcontrol. The prostaglandin is injected or applied in a feed at doses of0.1-100 mg. per animal and may be combined with other agents such assteroids. Dosing schedules will depend on the species treated. Forexample, mares are given the prostaglandin derivative 5 to 8 days afterovulation and return to estrus. Cattle are treated at regular intervalsover a 3 week period to advantageously bring all into estrus at the sametime.

These compounds including the salts increase the flow of blood in themammalian kidney, thereby increasing volume and electrolyte content ofthe urine. For that reason, these compounds are useful in managing casesof renal dysfunction, especially those involving blockage of the renalvascular bed. Illustratively, these compounds are useful to alleviateand correct caes of edema resulting, for example, from massive surfaceburns, and in the management of shock. For these purposes, thesecompounds are preferably first administered by intraveous injection at adose in the range 10 to 1000 μg. per kg. of body weight or byintravenous infusion at a dose in the range 0.1 to 20 μg. per kg. ofbody weight per minute until the desired effect is obtained. Subsequentdoses are given by intravenous, intramuscular, or subcutaneous injectionor infusion in the range 0.05 to 2 mg. per kg. of body weight per day.

The compounds so cited above as promoters and acceleraters of growth ofepidermal cells and keratin are useful in animals, including humans,useful domestic animals, pets, zoological specimens, and laboratoryanimals for this purpose. For this reason, these compounds are useful topromote and accelerate healing of skin which has been damaged, forexample, by burns, wounds, and abrasions, and after surgery. Thesecompounds are also useful to promote and accelerate adherence and growthof skin autografts, especially small, deep (Davis) grafts which areintended to cover skinless areas by subsequent outward growth ratherthan initially, and to retard rejection of homografts.

For the above purposes, these compounds are preferably administeredtopically at or near the cite where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet resins, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separately or in combination with the usual infusions of blood, plasma,or substitutes thereof. Alernative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 1to 500 μg per ml. of the prostaglandin derivative. Especially fortopical use, these compounds are useful in combination with antibiotics,for example, gentamycin, neomycin, polymixin, bacitracin, spectinomycin,and oxytetracycline, with other antibacterials, for example, mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, andwith corticoid steroids, for example, hydrocortisone, prednisolone,methylprednisolone, and fluprednisolone, each of those being used in thecombination at the usual concentration suitable for its use alone.

These prostaglandin derivatives are useful for treating proliferatingskin diseases of man and domesticated animals, including psoriasis,atopic dermatitis, non-specific dermatitis, primary irritant contactdermatitis, allergic contact dermatitis, basal and squamous cellcarcinomas of the skin, lamellar ichthyosis, epidermolytichyperkeratosis, premalignant sun-induced keratosis, non-malignantkeratosis, acne, and seborrheic dermatitis in humans and atopicdermatitis and mange in domesticated animals. These compounds alleviatethe symtoms of these proliferative skin diseases: psoriasis, forexample, being alleviated when a scale-free psoriasis lesion isnoticeably decreased in thickness or noticeably but incompletely clearedor completely cleared.

These compounds are applied topically as compositions including asuitable pharmaceutical carrier, for example, as an ointment, lotion,paste, jelly, spray, or aerosol, using typical bases such as petrolatum,lanolin, polyethylene glycols, and alcohols. These compounds, as theactive ingredients, constitute from about 0.1% to about 15% by weight ofthe composition, preferably from about 0.5% to about 2%. In addition tooptical administration, injection may be employed, as intradermally,intra- or peri-lesionally, or subcutaneously, using appropriate sterilesaline compositions.

These compounds are useful as anti-inflammatory agents for inhibitingchronic inflammation in mammals including the swelling and otherunpleasant effects thereof using methods of treatment and dosagesgenerally in accord with U.S. Pat. No. 3,885,041, which patent isincorporated herein by reference.

Many of the biological responses known for these 6-keto prostaglandinderivatives are also known for the older prostaglandin compounds.However, these derivatives are surprisingly more specific with regard topotency in causing prostaglandin-like biological responses. Each ofthese novel derivatives is therefore useful in place of the knownprostaglandin-type compounds for at least one of the abovepharmacological purposes and, moreover, is surprisingly and unexpectedlymore useful for that purpose because it causes smaller and fewerundesired side effects than the known prostaglandins.

Furthermore, these novel compounds are administered effectively orally,sublingually, intravaginally, buccally, or rectally, in addition tousual intravenous, intramuscular, or subcutaneous injection or infusionmethods used for the known prostaglandins. These qualities areadvanageous because they facilitate maintaining unifom levels of thesecompounds in the body with fewer, shorter, or smaller doses, and makepossible self-administration by the patient.

There are furthr provided the various processes for preparing the 6-ketocompounds of formula I. Thus, one process comprises the steps ofstarting with a compound of the formula ##STR52## and

(a) transforming that starting compound to a compound of the formula##STR53##

(b) subjecting the product of step (a) to oxidation to form a compoundof the formula ##STR54## and (c) transforming the product of step (b) toa compound of the formula ##STR55##

Reference to Chart A herein will make clear the steps of that process.

The starting materials of formula III are not the subject of thisinvention but will be described at a later point in this application.The 6-keto compounds of formula III are in equilibrium with andtherefore accompanied by hemi-ketal compounds of the formula ##STR56##

In step "a" of Chart A the starting material III is transformed to acorresponding formula-IV compound. ##STR57##

When the blocking group R₂₁ is Q₁, R₂₂ and R₂₃ in tetrahydropyranyl ortetrahydrofuranyl, the appropriate reagent, e.g. 2,3-dihydropyran or2,3-dihydrofuran, is used in an inert solvent such as dichloromethane inthe presence of an acid condensing agent such as p-toluenesulfonic acidor pyridine hydrochloride. The reagent is used in slight excess,preferably 1.0 to 1.2 times theory, and the reaction is carried out atabout 20-50° C.

When R₂₁ is of the formula ##STR58## as defined herein, including1-ethoxyethyl, the appropriate reagent is a vinyl ether, e.g. ethylvinyl ether, isopropenyl methyl ether, isobutyl vinyl ether, or anyvinyl ether of the formula R₁₄ --O--C(R₁₅)═CR₁₆ R₁₇ wherein R₁₄, R₁₅,R₁₆, and R₁₇ are as defined above; or an unsaturated cyclic orheterocyclic compound, e.g. -cyclohex-1-yl methyl ether ##STR59## or5,6-dihydro-4-methoxy-2H-pyran ##STR60## See C.B. Reese et al, J. Am.Chem. Soc. 89, 3366 (1967). The reaction conditions for such vinylethers and unsaturates are similar to those for dihydropyran above.

The 6-keto formula-IV compound, now with blocking groups at C-11 andC-15, is also accompanied by hemi-ketal compounds derived from formulaXX but now block at C-11 and C-15. It is possible that the C-6 hydroxylis also reactive to the blocking agent. Whether or not the C-6 hydroxylis blocked is immaterial to the success of the following step (b). Anyether groups at C-6 are readily removed in the presence of the reagentsused in step (b). Any hemi-ketal therefore equilibrates readily andrapidly to the 6-keto compound IV and is transformed to the formula-Vcomound in step (b).

In step "b" of Chart A, the hydroxyl on the cyclopentane ring at the C-9position of the formula-IV compound is oxidized to the oxo group of theformula-V compound.

Oxidation reagents useful for this transformation are known in the art.A useful reagent for this purpose is the Jones reagent, i.e., acidifiedchromic acid. See J. Chem. Soc. 39 (1946). A slight excess beyond theamount necessary to oxidize the C-9 secondary hydroxy groups of theformula-IV reactant is used. Acetone is a suitable diluent for thispurpose. Reaction temperature at least as low as about 0° C. should beused. Preferred reaction temperatures are in the range 0° to -50° C.Another useful reagent for this purpose is the Collins reagent, i.e.chromium trioxide in pyridine. See J. C. Collins et al., TetrahedronLett., 3363 (1968). Dichloromethane is a suitable diluent for thispurpose. Reaction temperatures of below 30° C. should be used. Preferredreaction temperatures are in the range 0° to +30° C. The oxidationproceeds rapidly and is usually complete in about 5 to 20 minutes.

Examples of other oxidation reagents useful for this transformation aresilver carbonate on Celite (Chem. Commun. 1102 (1969)), mixtures ofchromium trioxide and pyridine J. Am. Chem. Soc. 75, 422 (1953) andTetrahedron, 18, 1351 (1962)), t-butylchromate in pyridine (Biochem. J.84, 195 (1962)), mixtures of sulfur trioxide in pyridine anddimethylsulfoxide (J. Am. Chem. Soc. 89, 5505 (1967)), and mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87,5661 (1965)).

In step "c" of Chart A, the blocking groups R₂₁ are replaced withhydrogen by acid hydrolysis, thereby forming product VI. Generalprocedures are known in the art. For the tetrahydropyranyl groups, forexample, the formula-V compound is contacted with methanol-HCl or withacetic acid-water-tetrahydrofuran at 40°-55° C.

Thereafter, additional compounds within the scope of formula I, such aspharmacologically acceptable salts, are optionally made from formula-VIacids by processes described herein or known in the art.

As used in the formulas of Chart A and elsewhere herein, examples ofalkyl of one to 4 carbon atoms, inclusive, are methyl, ethyl, propyl,butyl, and isomeric forms thereof. Examples of alkyl of one to 7 carbonatoms, inclusive, are, in addition, pentyl, hexyl, heptyl, and isomericforms thereof. Examples of alkyl of one to 12 carbon atoms, inclusive,are, in addition, octyl, nonyl, decyl, undecyl, dodecyl, and isomericforms thereof. Examples of alkyl of one to 18 carbon atoms are, inaddition, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,octadecyl, and isomeric forms thereof.

Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, whichincludes alkyl-substituted cycloalkyl, are

cyclopropyl,

2-methylcyclopropyl,

2,2-dimethylcyclopropyl,

2,3-diethylcyclopropyl,

2-butylcyclopropyl,

cyclobutyl,

2-methylcyclobutyl,

3-propylcyclobutyl,

2,3,4-triethylcyclobutyl,

cyclopentyl,

2,2-dimethylcyclopentyl,

3-pentylcyclopentyl,

3-tert-butylcyclopentyl,

cyclohexyl,

4-tert-butylcyclohexyl,

3-isopropylcyclohexyl,

2,2-dimethylcyclohexyl,

cycloheptyl,

cyclooctyl,

cyclononyl,

and cyclodecyl.

Examples of phenylalkyl of 7 to 10 carbon atoms, inclusive, are

benzyl,

1-phenylethyl,

2-phenylethyl,

2-phenylpropyl,

4-phenylbutyl, and

3-phenylbutyl.

Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are, in addition

2-(1-naphthylethyl),

and 1-(2-naphthylmethyl).

Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4carbon atoms, inclusive are

p-chlorophenyl,

m-chlorophenyl,

o-chlorophenyl,

2,4-dichlorophenyl,

2,4,6-trichlorophenyl,

p-tolyl,

m-tolyl,

o-tolyl,

p-ethylphenyl,

p-tert-butylphenyl,

2,5-dimethylphenyl,

4-chloro-2-methylphenyl,

and 2,4-dichloro-3-methylphenyl.

Examples of alkylene of one to 9 carbon atoms, inclusive, with one to 5carbon atoms, inclusive, in the chain, within the scope of C_(g) H_(2g)as defined herein, are methylene, ethylene, trimethylene,tetramethylene, and pentamethylene, and those alkylene with one or morealkyl substituents on one or more carbon atoms thereof, e.g.--CH(CH₃)--, --C(CH₃)₂ --, --CH(CH₂ CH₃)--, --CH₂ --CH(CH₃)--,--CH(CH₃)--CH(CH₃)--, --CH₂ --(CH₃)₂ --, --CH₂ --CH(CH₃)--CH₃ --, --CH₂--CH₂ --CH(CH₂ CH₂ CH₃)--, --CH(CH₃)--CH(CH₃)--CH₂ --CH₂ --, --CH₂ CH₂--CH₂ --C(CH₃)₂ --CH₂, and --CH₂ --CH₂ --CH₂ --CH₂ --CH(CH₃)--. Examplesof alkylene of one to 9 carbon atoms, inclusive, substituted with zero,one, or 2 fluoro, with one to 6 carbon atoms in the chain, within thescope of C_(j) H_(2j) as defined herein, are those given above for C_(g)H_(2g) and hexamethylene, including hexamethylene with one or more alkylsubstituents on one or more carbon atoms thereof, and including thosealkylene groups with one or 2 fluoro substituents on one or 2 carbonatoms thereof, e.g. --CHF--CH₂ --, --CHF--CHF--, --CH₂ --CH₂ --CF₂ --,--CH₂ --CHF--CH₂ --, --CH₂ --CH₂ --CF(CH₃)--, --CH₂ --CH₂ --CF₂ --CH₂,--CH(CH₃)--CH₂ --CH₂ --CHF--, --CH₂ --CH₂ --CH₂ --CH₂ --CF₂ --,--CHF--CH₂ CH₂ --CH₂ --CH₂ --CHF--, --CF₂ --CH₂ --CH₂ --CH₂ --CH₂ --CH₂--, --CH₂ --CH.sub. 2 --CH₂ --CF₂ --CH₂ --CH₂ --, and --CH₂ --CH₂ --CH₂--CH₂ --CH₂ --CF₂.

Examples of ##STR61## as defined herein are phenyl,

(o-, m-, or p-)tolyl,

(o-, m-, or p-)ethylphenyl,

(o-, m-, or p-)propylphenyl,

(o-, m-, or p-)butylphenyl,

(o-, m-, or p-)isobutylphenyl,

(o-, m-, or p-)tert-butylphenyl,

2,3-xylyl,

2,4-xylyl,

2,5-xylyl,

2,6-xylyl,

3,4-xylyl,

2,6-diethylphenyl,

2-ethyl-p-tolyl,

4-ethyl-o-tolyl,

5-ethyl-m-tolyl,

2-propyl-(o-, m-, or p-)tolyl,

4-butyl-m-tolyl,

6-tert-butyl-m-tolyl,

4-isopropyl-2,6-xylyl,

3-propyl-4-ethylphenyl,

(2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5-)trimethylphenyl,

(O-, m-, or p-)fluorophenyl,

2-fluoro-(o-, m-, or p-)tolyl,

4-fluoro-2,5-xylyl,

(2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl,

(o-, m-, or p-)chlorophenyl,

2-chloro-p-tolyl,

(3-, 4-, 5-, or 6-)chloro-o-tolyl,

4-chloro-2-propylphenyl,

2-isopropyl-4-chlorophenyl,

4-chloro-3,5-xylyl,

(2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyl,

4-chloro-3-fluorophenyl,

(3-, or 4-)chloro-2-fluorophenyl,

α,α,α-trifluoro-(o-, m-, or p-)tolyl,

(o-, m-, or p-)methoxyphenyl,

(o-, m-, or p-(ethoxyphenyl,

(4- or 5-)chloro-2-methoxyphenyl, and

2,4-dichloro(5- or 6-)methoxyphenyl.

Included in the compounds of formula I are the pharmacologicallyacceptable salts when R₃ is a cation. Such pharmacologically acceptablesalts useful for the purposes described above are those withpharmacologically acceptable metal cations, ammonium, amine cations, orquaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine,2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and thelike, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol-tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tertamylphenyl)diethanolamine, galactamine,N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

Salts containing pharmacologically acceptable cations are prepared fromthe final formula-VI compounds in free acid form, i.e. wherein R₁₉ is--COOH, by neutralization with appropriate amounts of the correspondinginorganic or organic base, examples of which correspond to the cationsand amines listed above. These transformations are carried out by avariety of procedures known in the art to be generally useful for thepreparation of inorganic, i.e., metal or ammonium, salts, amine acidaddition salts, and quaternary ammonium salts. The choice of proceduredepends in part upon the solubility characteristics of the particularsalt to be prepared. In the case of the inorganic salts, it is usuallysuitable to dissolve the formula-VI acid in water containing thestoichiometric amount of a hydroxide, carbonate, or bicarbonatecorresponding to the inorganic salt desired. For example, such use ofsodium hydroxide, sodium carbonate, or sodium bicarbonate gives asolution of the sodium salt. Evaporation of the water or addition of awater-miscible solvent of moderate polarity, for example, a loweralkanol or a lower alkanone, gives the solid inorganic salt if that formis desired. Amine and quaternary ammonium salts are prepared by similarmethods using appropriate solvents.

As discussed above, the compounds of formula I are administered invarious ways for various purposes; e.g., intravenously, intramuscularly,subcutaneously, orally, intravaginally, rectally, buccally,sublingually, topically, and in the form of sterile implants forprolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose, it is advantageous because ofincreased water solubility that R₃ in the formula I compound be hydrogenor a pharmacologically acceptable cation. For subcutaneous orintramusclar injection, sterile solutions or suspensions of the acid,salt, or ester form in aqueous or non-aqueous media are used. Tablets,capsules, and liquid preparations such as syrups, elixirs, and simplesolutions, with the usual pharmaceutical carriers are used for oralsublingual administration. For rectal or vaginal administrationsuppositories prepared as known in the art are used. For tissueimplants, a sterile tablet or silicone rubber capsule or other objectcontaining or impregnated with the substance is used.

Various esters of formula I within the scope of R₃ are optionallyprepared from the corresponding acids of formula I, the correspondingacids of formula I, i.e. wherein R₁ is --COOH, by methods known in theart. For example, the alkyl, cycloalkyl, and aralkyl esters are preparedby interaction of said acids with the appropriate diazohydrocarbon. Forexample, when diazomethane is used, the methyl esters are produced.Similar use of diazoethane, diazobutane, -diazo-2-ethylhexane,diazocyclohexane, and phenyldiazomethane, for example, gives the ethyl,butyl, 2-ethylhexyl, cyclohexyl, and benzyl esters, respectively. Ofthese esters, the methyl or ethyl are preferred.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbons are known in the art or can be prepared by methodsknown in the art. See, for example Organic Reactions, John Wiley & Sons,Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxyl moiety of thenovel compounds of formula I comprises transformations of the free acidto the corresponding silver salt, followed by interaction of that saltwith an alkyl iodide. Examples of suitable iodides are methyl iodide,ethyl iodide, butyl iodide, isobutyl iodide, tertbutyl iodide,cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phenethyl iodide,and the like. The silver salts are prepared by conventional methods, forexample, by dissolving the acid in cold dilute aqueous ammonia,evaporating the excess ammonia at reduced pressure, and then adding thestoichiometric amount of silver nitrate.

The phenyl and substituted phenyl esters of the formula I compounds areprepared by silylating the acid to protect the hydroxy groups, forexample, replacing each --OH with --O--Si--(CH₃)₃. Doing that may alsochange --COOH to --COO--Si--(CH₃)₃. A brief treatment of the silylatedcompound with water will change --COO--Si--(CH₃)₃ back to --COOH.Procedures for this silylation are known in the art and are available.Then, treatment of the silylated compound with oxalyl chloride gives theacid chloride which is reacted with phenol or the appropriatesubstituted phenol to give a silylated phenyl or substituted phenylester. Then the silyl groups, e.g., --O--Si--(CH₃)₃ are changed back to-OH by treatment with dilute acetic acid. Procedures for thesetransformations are known in the art.

A preferred method for substituted phenyl esters is that disclosed inU.S. Pat. No. 3,890,372 in which a mixed anhydride is reacted with anappropriate phenol or naphthol. The anhydride is formed from the acidwith isobutylchloroformate in the presence of a tertiary amine.

Phenacyl-type esters are prepared from the acid using a phenacylbromide, for example p-phenylphenacyl bromide, in the presence of atertiary amine. See for example U.S. Pat. No. 3,984,454, GermanOffenlag. No. 2,535,693, and Derwent Farmdoc No. 16828X.

Compounds in which R₁ is ##STR62## are conveniently prepared from theformula-VI products which are acids, i.e. R₁ is --COOH. The sequence ofreactions is described hereinafter in the section on"2-Decarboxy-2-amino PGF Compounds". For example, the acid compound isconverted to a mixed anhydride and thence to an amide. Carboxylreduction of the amide yields the amine. Alternatively the mixedanhydride is converted to an azide, thence to a urethane from which thesubstituted amines, primary or secondary, are readily available bymethods known in the art.

Also included in the compounds of this invention are the loweralkanoates, wherein "lower alkanoate" refers to an ester of an alkanoicacid of one to 8 carbon atoms, inclusive. Examples of such alkanoicacids are formic, acetic, propanoic, butanoic, pentanoic, hexanoic,heptanoic, and octanoic acids, and isomeric forms thereof.

The formula-VI compounds prepared by the process described above aretransformed to lower alkanoates by interaction with a carboxyacylatingagent, preferably the anhydride of a lower alkanoic acid, i.e., analkanoic acid of one to 8 carbon atoms, inclusive. For example, use ofacetic anhydride gives the corresponding diacetate. Similar use ofpropionic anhydride, isobutyric anhydride, and hexanoic acid anhydridegives the corresponding carboxyacylates.

The carboxyacylation is advantageously carried out by mixing the hydroxycompound and the acid anhydride, preferably in the presence of atertiary amine such as pyridine or triethylamine. A substantial excessof the anhydride is used, preferably about 10 to about 1,000 moles ofanhydride per mole of the hydroxy compound reactant. The excessanhydride serves as a reaction diluent and solvent. An inert organicdiluent, for example dioxane, can also be added. It is preferred to useenough of the tertiary amine to neutralize the carboxylic acid producedby the reaction, as well as any free carboxyl groups present in thehydroxy compound reactant.

The carboxyacylation reaction is preferably carried out in the rangeabout 0° to about 100° C. The necessary reaction time will depend onsuch factors as the reaction temperature, and the nature of theanhydride. For acetic anhydride, pyridine, and a 25° C. reactiontemperature, a 12-to-24-hour reaction time is used.

The carboxyacylated product is isolated from the reaction mixture byconventional methods. For example, the excess anhydride is decomposedwith water, and the resulting mixture acidified and then extracted witha solvent such as diethyl ether. The desired carboxylate is recoveredfrom the diethyl ether extract by evaporation. The carboxylate is thenpurified by conventional methods, advantageously by chromatography.

Another process for the formula-I 6-keto compounds comprises the stepsof starting with a halo ether of the formula ##STR63## and

(a) transforming that starting material to a compound of the formula##STR64##

(b) subjecting the product of step "a" to dehydrohalogenation andhydrolysis to form a compound of the formula ##STR65##

(c) oxidizing the product of step "b" to a compound of the formula##STR66## and (d) hydrolyzing the product of step "c" to form a compoundof the formula ##STR67## Thereafter, salts within the scope of theformula I are prepared from formula-VI acids.

Chart B, herein, shows the steps of this process. The starting materialsof formula VII are not the subject of this invention but will bedescribed below. ##STR68##

In the first step "d" of Chart B, the starting material VII istransformed to a corresponding formula-VIII compound. The blocking groupR₂₁ in Q', R₂₂ , and R₂₃ may be the same as or different than theblocking group R₂₁ in Chart A, but the details as to reagents andprocedures have already been described above for Chart A, step "a".

In step "e" of Chart B, the formula-VIII halo compound is subjected todehydrohalogenation and hydrolysis to form the formula IV 6-ketoPGF-type compound. In one method a halo compound VIII is contacted withsilver carbonate and perchloric acid in an organic medium such astetrahydrofuran. The reaction is followed with TLC (thin layerchromatography) to determine completion, normally 15-24 hr. at about 25°C. The reaction is preferably done in absence of light.

In another method the halo compound VIII is treated with adehydrohalogenation reagent known in the art. See for example Fieser andFieser "Reagents for Organic Synthesis", p. 1308, John Wiley and Sons,Inc., New York, N.Y. (1967). Useful in this purpose are tertiary amines,preferably.

1,5-diazabicyclo[4.3.0]nonene-5 ("DBN")

1,4-diazabicyclo[2.2.2]octane ("DABCO") and

1,5-diazabicyclo[5.4.0]undecene-5("DBU").

The reaction is carried out in an inert medium such as dimethylformamideand is followed by TLC, to show the disappearance of starting material.The reaction proceeds at 25° C. and can be accelerated at 40°-50° C. Anintermediate enol ether is thereby obtained, preferably purified bywashing free of amine, and thereafter treated with dilute aqueous acid,preferably acetic acid, until the more polar formula-IV compound isformed as shown by TLC.

The formula-IV 6keto compounds are in equilibrium with and thereforeaccompanied by hemi-ketals of the formula ##STR69## Such hemi-ketalsequilibrate rapidly to the 6-keto compound IV during the oxidation andare transformed to the formula-V compound in step (f).

Thereafter in steps "f" and "g" the product above is oxidized to theformula-V compound, and finally hydrolyzed to yield the formula-VIproduct. The reagents and conditions for these steps have already beendescribed above for Chart A, steps "b" and "c".

There is further disclosed a process for preparing6-keto-13,14-didehydro-PGE-type compounds of the formula ##STR70## whichcomprises the steps of starting with a compound of the formula ##STR71##and

(a) subjecting that starting material to selective halogenation andselective monodehydrohalogenation to form a 5,6,14-trihalo compoundrepresented by the formula ##STR72##

(b) subjecting the product of step "a" to reduction to form a compoundof the formula ##STR73##

(c) subjecting the product of step (b) to selective dehalogenation toform a compound of the formula ##STR74##

(d) halogenating and cyclizing to form a compound of the formula##STR75##

(e) transforming the product of step "d" to a compound of the formula##STR76##

(f) transforming the product of step "e" to a compound of the formula##STR77##

(g) subjecting the product of step (f) to oxidation to form a compoundof the formula ##STR78##

(h) hydrolyzing the product of step "g" to replace the blocking groupsR₂₁ with hydrogen and thereby form 6-keto-13,14-didehydro PGE-typecompounds of formula X.

Chart C, herein, shows the steps of that process. The starting materialsof formula XI are 15-oxo PGF type compounds known in the art oravailable by methods described herein or known in the art. For examplesee U.S. Pat. No. 3,728,382. It is immaterial whether 5,6-cis or5,6-trans compounds are used as either one will ultimately yield thedesired formula-X compound.

In the first step "h" of Chart C the formula-XII trihalo compound isprepared, for example by reaction of the formula-XI compound withpyridinium hydrobromide perbromide in pyridine. Other halogenatingagents are useful, e.g. N-bromo- or N-chloro-succinimide. Other tertiaryamines are useful for the selective monodehydrohalogenation.

In step "i", the formula-XIII compound is obtained as a mixture of alphaand beta hydroxy isomers by reduction of XII. For this reduction, use ismade of any of the known ketonic carbonyl reducing agents which do notreduce ester or acid groups or carbon-carbon double bonds when thelatter is undesirable. Examples of those are the metal borohydrides,especially sodium, potassium, and zinc borohydrides, lithium(tri-tert-tuoxy) aluminum hydride, metal trialkoxy borohydrides, e.g.,sodium trimethoxyborohydride, lithium borohydride, or diisobutylaluminum hydride. For production of the preferred natural-configurationprostaglandin derivatives, the alpha form of the formula-XIII compoundis separated from the beta isomer by silica gel chromatography usingmethods known in the art. ##STR79##

In step "j" the C-5 and C-6 halogen atoms are removed by selectivedehalogenation for example by contact with zinc in methanolic ammoniumchloride, to yield the formula-XIV monohalo compound. Other monohalocompounds within the scope of XIV are known in the art. See for exampleU.S. Pat. No. 4,029,681.

In step "k" the formula-XIV compound is halogenated and cyclized to formthe formula-XV halo ether. For this purpose there are various methodsavailable. For the iodo compounds there may be used an aqueous systemcontaining iodine, potassium iodide, and an alkali carbonate orbicarbonate, or an organic solvent system such as dichloromethanecontaining iodine in the presence of an alkali metal carbonate. Thereaction is carried out at temperatures below 25° C., preferably about0°-5° C. for 10-20 hours. Thereafter the reaction is quenched withsodium sulfite and sodium carbonate and the formula-XV compoundseparated from the reaction mixture.

From the bromo compounds, N-bromosuccinimide or N-bromoacetamide areuseful. See Fieser et al., Reagents for Organic Synthesis, Vol. 1, pp.74 and 78, Vol. IV, p. 51, John Wiley and Sons, Inc., N.Y. For thechloro compound various methods are available, for example exchange ofbromo with chloro using the silver salt of chlorodifluoroacetic acid.See I.T. Harrison et al., Compendium of Organic Synthetic Methods, p.346, 1971, Wiley Interscience, N.Y.

The formula-XV halo compounds are obtained as two isomers, one in minorand the other in major quantity, differing in their chromatographicmobility. These C-5 and C-6 isomers are separable by silica gelchromatography, but are normally not separated, as either one yields thedesired formula XVII, XVIII, and X compounds.

In step "l" the formula-XVI compound is formed as known in the art ordescribed herein, replacing hydrogen atoms in free hydroxyls in Q₂, R₁₉,and R₇ with blocking groups R₂₁.

In step "m" the formula-XVI compound is treated with adehydrohalogenation reagent preferably potassium t-butoxide, to form theformula-XVII 6-keto-PGF-type compound.

The remaining steps in the process, "n" and "o", are analogous to thosein Chart A. For step "n", the formula-XVII compound is subjected tooxidation as in step "b" of Chart A. In step "o" the formula-XVIIIcompound is hydrolyzed to remove blocking groups as in step "c" of ChartA.

Referring now to Chart D, there is shown a source of the formula-III6-keto-PGF₁α -type starting materials for Chart A and the formula-VIIhalo ether starting materials for Chart B. ##STR80##

The starting materials of formula XIX are known in the art or arereadily available by processes known in the art. For example, as toPGF₂α see U.S. Pat. No. 3,706,789; as to 15-methyl- and 15-ethyl-PGF₂α,see U.S. Pat. No. 3,728,382; as to 16,16-dimethyl-PGF₂α, see U.S. Pat.No. 3,903,131; as to 16,16-difluoro-PGF₂α compounds, see U.S. Pat. Nos.3,962,293 and 3,969,380; as to 16-phenoxy-17,18,19,20-tetranor-PGF₂α,see Derwent Farmdoc No. 73279U; as to 17-phenyl-18,19,20-trinor-PGF₂α,see Derwent Farmdoc No. 31279T; as to 11-deoxy-PGF₂α, see DerwentFarmdoc No. 10695V; as to 2a,2b-dihomo-PGF₂α, see Derwent Farmdoc No.61412S and U.S. Pat. Nos. 3,852,316 and 3,974,159; as to 3-oxo-PGF₂α,see U.S. Pat. No. 3,923,861; as to3-oxa-17-phenyl-18,19,20-trinor-PGF₂α, see U.S. Pat. No. 3,931,289; asto substituted phenacyl esters, see Derwent Farmdoc No. 16828X; as tosubstituted phenyl esters, see U.S. Pat. No. 3,890,372; as to C-1-alcohols, i.e. 2-decarboxy-2-hydroxymethyl compounds, see U.S. Pat. No.3,636,120; as to C-2 tetrazolyl derivatives, see U.S. Pat. No.3,932,389; as to Δ2-PGF₂α see Derwent Farmdoc No. 46497W and Ger. Offen.No. 2,460,285; as to 5,6-trans-PGF₂α, see U.S. Pat. No. 3,759,978; as to2,2-dimethyl-PGF₂α analogs, see Derwent Farmdoc No. 59033T and Ger.Offen. No. 2,209,039; as to 11β-PGF₂α compounds, see U.S. Pat. No.3,890,371; as to 11-deoxy-PGF₂α, see Derwent Farmdoc No. 10695V; as to11-deoxy-11-hydroxymethyl-PGF₂α, see U.S. Pat. Nos. 3,931,282 and3,950,363; as to 16-methylene-PGF₂α, see Derwent Farmdoc No. 19594W andGer. Offen. No. 2,440,919; as to 17,18-didehydro-PGF₂α compounds, seeU.S. Pat. No. 3,920,726; as to 3-(or 4-)oxa-17,18-didehydro-PGF.sub. 2αcompounds, see U.S. Pat. No. 3,920,723; as to 15-oxo-PGF₂α, see U.S.Pat. No. 3,728,382; as to 15-deoxy-PGF₂α, see Derwent Farmdoc No. 9239W;as to 13,14-cis compounds, see U.S. Pat. No. 3,932,479; as to11-deoxy-15-deoxy-PGF₂α see Derwent Farmdoc No. 5694U; as toω-homo-PGF₂α compounds, see Derwent Farmdoc No. 4728W; and as to2,2-difluoro-PFG₂α compounds, see Derwent Farmdoc No. 67438R.

As to 2-decarboxy-2-amino-PGF₂α compounds, see that section incorporatedherein, taken from a prior-filed, commonly-owned U.S. patentapplication.

In step "p" of Chart D, the starting material XIX is subjected tohalogenation and cyclization to yield the formula-VII halo compounds.For this purpose there is used any of the halogenating methods describedabove for step "k" of Chart C. Here also it is immaterial whether5,6-cis or 5,6-trans compounds of formula-XIX are used or which isomersof the formula-VII halo compounds are used.

In step "q" of Chart D the halo compound is converted to the mixture ofcompounds III and XX by dehydrohalogenation and hydrolysis. See forexample the methods of Chart B, step "e" above.

Chart E, herein, shows the steps of a method for preparing2-decarboxy-2-hydroxymethyl compounds of the formula ##STR81##

The formula-XXII starting materials for Chart E are lactoneintermediates known in the art or readily available by methods known inthe art. For example when R₃₆ is ##STR82## and when R₄ is n-pentyl, seeCorey et al., J. Am. Chem. Soc. 92, 397 (1970). When R₄ is ##STR83##wherein R₅ and R₆ are methyl or ethyl, see U.S. Pat. No. 3,954,833. WhenR₅ and R₆ are fluoro, see U.S. Pat. No. 3,962,293. When Q₁ is ##STR84##see U.S. Pat. Nos. 3,864,387 and 3,931,279.

When R₃₆ is ##STR85## these 11β lactones ae obtained by isomerizing acorresponding lactone having the 11α configuration, with suitableblocking at the C-15 position if desired, by methods known in the art,such as by way of the 11-mesylate or 11-tosylate.

When R₃₆ is ##STR86## and R₄ is alkyl, see U.S. Pat. No. 3,931,279 andDerwent Farmdoc Abstract No. 10695V; when R₄ is phenyl-substituted, alsosee U.S. Pat. No. 3,931,279.

When R₃₆ is ##STR87## see Ger. Offen. No. 2,437,622 and Derwent FarmdocNo. 12714W.

For example a compound of the formula ##STR88## is reduced at the --COOHposition to the corresponding --CH₂ OH compound using diborane, andthereafter reacted with a suitable blocking agent.

In step "r" of Chart E the starting material XXII is condensed with analkynyllithium compound of the formula

    Li--C.tbd.C--(CH.sub.2).sub.f --C(R.sub.2).sub.2 --CH.sub.2 --O--Si(CH.sub.3).sub.3.                                  XXVII

see C. H. Lin et al. Synthetic Comm. 6, 503 (1976) and Lin J. Org. Chem.41, 4045 (1976). The lithium compound is conveniently prepared in situfrom the silylated alkyne by reaction with methyl- or butyllithium in anether such as diethylether or tetrahydrofuran. In working up the productthe silyl groups are readily removed to yield XXIII.

In step "s" the formula-XXIII compound is oxidized at the C-9 position,preferably with Jones reagent. In this step some of the C-1 alcoholgroups are also oxidized to carboxylic acid groups. These are nextmethylated with diazomethane to facilitate removal of the by-product bychromatography. Blocking groups R₂₁ are replaced with hydrogen in theconventional way, as by mild acid hydrolysis for THP, to yield theformula-XXIV compound.

In step "t" compound XXIV is reduced to the XXV compound withoutreducing C₁₃ -C₁₄ or C₁₇ -C₁₈ ethylenic bonds that are present. For thispurpose catalytic hydrogenation is useful, for example, over palladiumon barium sulfate.

Chart F, herein, shows the step of a method for preparing 6,15-diketocompounds of the formula ##STR89## The starting material is anequilibrium mixture of the formula-XXVIII 6keto-PGF₁α -type andformula-XXIX hemiketal compounds. See for example Johnson et al. J. Am.Chem. Soc. 99, 4182 (1977). ##STR90##

In step "u", the blocking groups R₂₁ are added, using methods describedherein or known in the art. With dihydropyran, for example, the mainproduct is the bis(THP ether).

In step "v" the free acid is formed by saponification of the carboxylicester groups and acidification.

In step "w" the blocked 6-keto-PGF₁α -type compound of formula XXXII isoxidized, for example with Jones reagent, to the formula-XXXIV6,15-diketo-PGE₁ -type compound.

Finally, in step "x" the blocking groups are removed in the conventionalway to obtain the formula-XXXV product.

Chart G shows the steps in a preferred method for preparing amides ofthe formula ##STR91## The starting materials of formula XXXVI are 5-haloacids within the scope of formula VII of Chart B herein.

In step "y" the formula-XXXVI halo acid is converted to amide XXXVII,e.g. by way of a mixed anhydride. For this purpose, compound XXXVI istreated with isobutyl chloroformate in the presence of a tertiary aminesuch as triethylamine and thereafter with an amine of the formulaHN(R₉)(R₂₈).

In step "z" the halo amide XXXVII is then subjected todehydrohalogenation and hydrolysis to obtain the formula-XXXVIIcompound. Silver carbonate and perchloric acid are useful for thispurpose. ##STR92##

In step "aa" the formula-XXXVIII 6-keto-PGF₁α -type compound, havingsuitable blocking groups at C-11 and C-15, is oxidized to a PGE₁ -typecompound by methods known in the art, for example using Jones reagent atabout -15° to -20° C.

Finally, in step "bb" the blocking groups are removed, to producecompound XL.

It should be understood that although the Charts have formulas drawnwith a specific configuration for the reactants and products, theprocedural steps are intended to apply not only to the other opticallyactive isomers, but also to mixtures, including racemic mixtures ormixtures of enantiomeric forms.

If optically active products are desired, optically active startingmaterials or intermediates are employed or, if racemic startingmaterials or intermediates are used, the products are resolved bymethods known in the art for prostaglandins.

The products formed from each step of the reaction are often mixturesand, as known to one skilled in the art, may be used as such for asucceeding step or, optionally, separated by conventional methods offractionation, column chromatography, liquid-liquid extraction, and thelike, before proceeding.

Compounds within the scope of formula I are transformed from one toanother by methods known in the art. Accordingly, a formula-I compoundwherein R₁₈ is ##STR93## is transformed to another formula-I compoundwherein R₁₈ is another ring within the scope of R₁₈ , for example an11-deoxy compound, by methods known or described herein. A compoundwherein R₁₈ is ##STR94## is transformed to one wherein R₁₈ is ##STR95##by acid dehydration. A compound wherein the C₁₃ -C₁₄ group "X" istrans-CH═CH-- is transformed by known methods to another compoundwherein the C₁₃ -C₁₄ group is cis-CH═CH--, --C.tbd.C--, or --CH₂ CH₂ --.For example, --C.tbd.C-- is obtained by selective bromination anddehydrobromination. A compound wherein the C₂ substituent is --COOR₃,e.g. a method ester, is transformed by known methods to another compoundhaving another C₂ substituent within the scope of R₁, as defined herein,for example --CH₂ OH or ##STR96##

Compounds of formula V (Chart A), XVIII (Chart C), XXIV (Chart E), XXXIV(Chart F), and XXXIX (Chart G) having blocking groups are useful asintermediates in the various processes for preparing other usefulcompounds as described herein or known in the art.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope offormula I are preferred. For example it is preferred that Q be ##STR97##wherein it is especially preferred that R₈ be hydrogen, or methyl.

When Q is ##STR98## it is preferred that R₈ be methyl.

Another preference for the compounds of formula I, as to R₁, is that R₃in --COOR₃ be either hydrogen or alkyl of one to 12 carbon atoms,inclusive, or a salt of a pharmacologically acceptable cation. Further,when R₃ is alkyl, it is more preferred that it be alkyl of one to 4carbon atoms, and especially methyl or ethyl.

For purposes of stability on long storage it is preferred for thecompounds of formula I that R₃ in --COOR₃ be amido-substituted phenyl orphenacyl as illustrated herein.

For oral administration of compounds I it is preferred that R₁ be##STR99## It is especially preferred that at least one of R₉ and R₂₈ behydrogen.

As to variations in D, it is preferred that "d" be 2, 3, or 4, andespecially 2. When both R₂ 's are fluoro, it is preferred that R₈ in Qbe methyl, or that R₄ be ##STR100##

As to variations in R₁₈ , it is preferred that R₁₈ be ##STR101##

When R₄ in the compounds of formula I is ##STR102## it is preferred thatC_(g) H_(2g) be alkylene of 2, 3, or 4 carbon atoms, and especially thatit be trimethylene. It is further preferred that R₅ and R₆ be hydrogen,methyl, ethyl, or fluoro, being the same or different. It is furtherpreferred, when R₅ and R₆ are not hydrogen, that both R₅ and R₆ bemethyl or fluoro. It is especially preferred that R₄ be n-pentyl,1,1-dimethylpentyl, or 1,1-difluoropentyl.

When R₄ in the compounds of formula I is ##STR103## it is preferred that"s" be either zero or one. When "s" is not zero, it is preferred that Tbe methyl, chloro, fluoro, trifluoromethyl, or methoxy with meta or paraattachment to the phenyl ring. When Z is oxa (--O--), it is preferredthat R₅ and R₆ be hydrogen, methyl, or ethyl, being the same ordifferent. It is further preferred, when R₅ and R₆ are not hydrogen,that both R₅ and R₆ be methyl. When Z is C_(j) H_(2j), it is preferredthat C_(j) H_(2j) be a valence bond, methylene, or ethylene, It isespecially preferred that R₄ be ##STR104##

With respect to Chart H a method is provided whereby the formula ClPGF₂α - or 11-deoxy-PGF₂α -type free acid is transformed to the various2-decarboxy-2-aminomethyl or 2-decarboxy-2-(substitutedamino)methyl-PGF.sub.α - or 11-deoxy-PGF.sub.α -type compounds offormulas CIV, CVI, CVII, CVIII, CIX, or CX.

By the procedure of Chart H the formula Cl compound is transformed to aformula CII mixed acid anhydride. These mixed anhydrides areconveniently prepared from the corresponding alkyl, aralkyl, phenyl, orsubstituted phenyl chloroformate in the presence of an organic base(e.g., triethylamine). Reaction diluents include water in combinationwith water miscible organic solvents (e.g., tetrahydrofuran). This mixedanhydride is then transformed to either the formula CIII PG-type, amideor formula CV PG-type, azide.

For preparation of the PGF₂α -type, amide (formula CIII) the formula CIImixed acid anhydride is reacted with liquid ammonia or ammoniumhydroxide.

Alternatively, the formula CIII compound is prepared from the formula CIfree acid by methods known in the art for transformation to carboxyacids to corresponding carboxyamides. For example, the free acid istransformed to a corresponding methyl ester (employing methods known inthe art; e.g., excess ethereal diazomethane), and a methyl ester thusprepared is transformed to the formula CIII amide employing the methodsdescribed for the transformation of the formula CII mixed acid anhydrideto the formula CIII amide. ##STR105##

Thereafter the formula CiV 2-decarboxy-2-aminomethyl-PGF₂α - or11-deoxy-PGF₂α -type compound is prepared from the formula CIII compoundby carbonyl reduction. Methods known in the art art are employed in thistransformation. For example, lithium aluminum hydride is convenientlyemployed.

The formula CII compound is alternatively used to prepare the formula CVazide. This reaction is conveniently carried out employing sodium azideby methods known in the art. See for example, Fieser and Fieser,Reagents for Organic Synthesis vol. 1, pgs. 1041-1043, wherein reagentsand reaction conditions for the azide formation are discussed.

Finally, the formula CVI urethane is prepared from the formula CV azidereaction with an alkanol, aralkanol, phenol or substituted phenol. Forexample, when methanol is employed the formula CVI compound is preparedwherein R₃₂ is methyl. This formula CVI PG-type product is then employedin the preparation of either the formula CVII or CVIII product.

In the preparation of the formula CVII primary amine from the formulaCVI urethane, methods known in the art are employed. Thus, for example,treatment of the formula CVII urethane with strong base at temperaturesabove 50° C. are employed. For example, sodium potassium or lithiumhydroxide is employed.

Alternatively, the formula CVI compound is employed in the preparationof the formula CVIII compound. Thus, when L₁ is alkyl the formula CVIIIcompound is prepared by reduction of the formula CVI urethane whereinR₃₂ is alkyl. For this purpose, lithium aluminum hydride is theconveniently employed reducing agent.

Thereafter, the formula CVIII product is used to prepare thecorresponding CIX urethane by reaction of the formula CVIII secondaryamine (wherein L₂ is alkyl) with an alkyl chloroformate. The reactionthus proceeds by methods known in the art for the preparation ofcarbamates from corresponding secondard amines. Finally, the formula CXproduct wherein L₂ and L₃ are both alkyl is prepared by reduction of theformula CIX carbamide. Accordingly, methods hereinabove described forthe preparation of the formula CVIII compound from the formula CVIcompound are used. Optionally, the various reaction steps herein may bepreceded by the employment of blocking groups according to R₂₁, thusnecessitating their subsequent hydrolysis in preparing each of thevarious products above. Methods described hereinabove for theintroduction and hydrolysis of blocking groups according to R₂₁ areemployed.

Finally, the processes described above for converting the formula CIIcompound to the formula CV compound and the various compoundsthereafter, result in shortening the 8α-side chain of the formula CIcompound by one carbon atom. Accordingly, the formula CI startingmaterial should be selected so as to compensate for the methylene groupwhich is consumed in the steps of the above synthesis. Thus, where a2a-homo-product is desired a corresponding formula CI 2a,2b-dihomostarting material must be employed.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is further illustrated by, but not limited to, thefollowing examples.

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin-Elmer model 421infrared spectrophotometer. Except when specified otherwise, undiluted(neat) samples are used.

The NMR spectra are recorded on a Varian A-60, A-60D, T-60 or XL-100spectrophotometer in deuterochloroform solutions with tetramethylsilaneas an internal standard.

Mass spectra are recorded on a Varian Model MAT CH7 Mass Spectrometer, aCEC Model 110B Double Focusing High Resolution Mass Spectrometer, or aLKB Model 9000 Gas Chromatograph-Mass Spectrometer (ionization voltage22 or 70 ev.), and samples are usually run as TMS (trimethylsilyl)derivatives.

"Brine", herein, refers to an aqueous saturated sodium chloridesolution.

"DBN", herein, refers to 1,5-diazabicyclo[ 4.3.0] nonene-5.

"DABCO", herein, refers to 1,4-diazabicyclo[2.2.2]octane.

"DBU", herein, refers to 1,5-diazabicyclo[5.4.0]undecene-5.

"DIBAL", herein, refers to diisobutylaluminum hydride.

"E" and "Z", herein, follow Blackwood et al., cited above.

"Florisil®", herein, is a chromatographic magnesium silicate produced bythe Floridin Co. See Fieser et al. "Reagents for Organic Synthesis" p.393 John Wiley and Sons, Inc., New York, N.Y. (1967).

"HPLC", herein, refers to high pressure liquid chromatography.

"Skellysolve B", herein, refers to mixed isomeric hexanes.

"THP", herein, refers to tetrahydropyran-2-yl.

"TLC", herein refers to thin layer chromatography.

"Concentrating", as used herein, refers to concentration under reducedpressure, preferably at less than 50 mm. and at temperatures below 35°C.

"Drying", as used herein, refers to contacting a compound, in solution,with an anhydrous agent such as sodium sulfate or magnesium sulfate toremove water and filtering to remove solids.

Silica gel chromatography, as used herein, is understood to includeelution, collection of fractions, and combination of those fractionsshown by TLC to contain the desired product free of starting materialand impurities.

The A-lX solvent system used in thin layer chromatography is made upfrom ethyl acetate-acetic acid- 2,2,4-trimethylpentane-water(90:20:50:100) according to M. Hamberg and B. Samuelsson, J. Biol. Chem.241, 247 (1966).

PREPARATION 1

5ξ-iodo-9-deoxy-6,9-epoxy-PGF₁α, Methyl Ester (Formula VII: D is -(CH₂)₃-, Q is ##STR106## R₄ is n-pentyl, is ##STR107## R₁₉ is -COOCH₃, and Xis trans-CH═CH-.

Refer to Chart D. A suspension of PGF₂α, methyl ester as its 11,15-bis(tetrahydropyranyl)ether (2.0 g.) in 23 ml. of water is treated withsodium bicarbonate (0.7 g.) and cooled in an ice bath. To the resultingsolution is added potassium iodide (1.93 g.) and iodine (2.82 g.) andstirring continued for 16 hr. at about 0° C. Thereafter a solution ofsodium sulfite (1.66 g.) and sodium carbonate (0.76 g.) in 10 ml. ofwater is added. After a few minutes the mixture is extracted withchloroform. The organic phase is washed with brine, dried over sodiumsulfate, and concentrated to yield mainly the bis(tetrahydropyranyl)ether of the title compound, 2.2 g., an oil. Hydrolysis of this ether inacetic acid-water-tetrahydrofuran (20:10:3) yields mainly the titlecompound, which is further purified by silica gel chromatography. R_(f)0.20 (TLC on silica gel in acetonedichlormethane (30:70)). The massspectral peaks for the formula-VII compound (TMS derivtive) are at 638,623, 607, 567, 548, 511, and 477.

Following the procedures of Preparation 1, as illustrated in Chart D,but replacing the formula-XIX starting material with the followingformula-XIX compounds or C-11 derivatives within the scope of formulaXIX:

15-methyl-PGF₂α

(15r)-15-methyl-PGF₂α

15-ethyl-PGF₂α

16,16-dimethyl-PGF₂α

16,16-difluoro-PGF₂α

16-phenoxy-17,18,19,20-tetranor-PGF₂α

17-phenyl-18,19,20-trinor-PGF₂α

11-deoxy-PGF₂α

2a2 b-Dihomo-PGF₂α

3-oxa-PGF₂α

3-oxa-17-phenyl-18,19,20-trinor-PGF₂α

there are obtained the corresponding formula-VII iodo compounds.

PREPARATION 2

6-keto-PGF₁α, Methyl Ester (Formula III, D, Q, R₄, R₁₈ , R₁₉, and X asdefined in Preparation 1).

Refer to Chart D. A solution of the formula-VII iodo compound, methylester (Preparation 1, 0.45 g.) in 20 ml. of tetrahydrofuran is treatedwith silver carbonate (0.250 g.) and perchloric acid (70%, 0.10 ml.),and stirred at about 25° C. for 24 hr. The mixture is diluted with 25ml. of ethyl acetate and the organic phase is washed with saturatedsodium carbonate solution and brine, dried, and concentrated to an oil,0.41 g. Separation by silica gel chromatography eluting with ethylacetate-Skellysolve B (3:1) yields the formula-III title compound as amore polar material than the formula-VII starting material. The productis an oil, 0.32 g., having R_(f) 0.38 (TLC on silica gel inacetonedichloromethane (1:1)); infrared spectral peak at 1740 cm⁻¹ forcarbonyl; NMR peaks at 5.5, 3.2-4.8, 3.7, 2.1-2.7 δ.

PREPARATION 3

5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, Mixed Isomers (Formula VII) and9-Deoxy-6ξ,9α-epoxy-6ξ-hydroxy-PGF₁ (Formula XX) and 6-keto-PGF₁α(Formula III).

A solution of the formula-VII iodo compound methyl ester (Preparation 1,1.0 g.) in 30 ml. of methanol is treated with 20 ml. of 3 N aqueouspotassium hydroxide at about 0° C. for about 5 min., then at about 25°C. for 2 hr. The mixture is acidified with 45 ml. of 2 N potassium acidsulfate and 50 ml. of water to pH 1.0, saturated with sodium chlorideand extracted with ethyl acetate. The organic phase is washed withbrine, dried over sodium sulfate and concentrated to an oil, 1.3 g. Theoil is subjected to silica gel chromatography, eluting withacetone-dichloromethane (30:70 to 50:50) to yield, first the formula-Vllfree acid compound and later, the mixed formula-III and -XX compounds asa more polar fraction.

The formula-VII compound is an oil, 0.33 g., having R_(f) 0.33 (TLC onsilica gel in acetone-dichloromethane (1:1) plus 2% acetic acid),[α]_(D) =+ 20° (C=0.992 in chloroform), infrared spectral peaks at 3360,2920, 2860, 2640, 1730, 1710, 1455, 1410, 1380, 1235, 1185, 1075, 1050,1015, 970, and 730 cm⁻¹, and mass spectral peaks (TMS derivative) at696.2554, 681, 625, 606, 569, 535, 479, and 173.

The mixture of 9-deoxy-6ξ, 9α-epoxy-6ξ-hydroxy-PGF₁ and 6-keto-PGF₁α isa solid 0.113 g., melting at 93°-98° C., containing no iodine, havingR_(f) 0.13 (TLC on silica gel in acetone-dichloromethane (1:1) plus 2%acetic acid) and having mass spectral peaks (TMS derivative) at 587,568, 553, 497, 485, 407, 395, 388, and 173.

Following the procedures of Preparations 2 and 3, but replacing theformula-VII iodo compound therein with those formula-VII iodo compoundsdescribed subsequent to Preparation 1, there are obtained thecorresponding formula-III and -XX compounds.

Following the procedures of Preparations 1, 2, and 3, as describedabove, but employing corresponding starting materials, there areprepared the

formula-VII 9-deoxy-6,9-epoxy-5-halo-PGF₁α -type compounds, includingiodo, bromo, and chloro compounds,

formula-III 6-keto-PGF₁α -type compounds, and

formula-XX 9-deoxy-6,9-epoxy-6-hydroxy-PGF₁α -type compounds

having the following structural features:

16-Methyl-;

16,16-Dimethyl-;

16-Fluoro-;

16,16-Difluoro-;

17-Phenyl-18,19,20-trinor-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor:;

17-(m-chlorophenyl)-18,19,20-trinor-;

17-(p-fluorophenyl)-18,19,20-trinor-;

16-Methyl-17-phenyl-18,19,20-trinor-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-;

16-Fluoro-17-phenyl-18,19,20-trinor-;

16,16-Difluoro-17-phenyl-18,19,20-trinor-;

16-Phenoxy-17,18,19,20-tetranor-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-;

16-(p-fluorophenoxy)-17,18,19,20-tetranor-;

16-Phenoxy-18,19,20-trinor-;

16-Methyl-16-phenoxy-18,19,20-trinor-;

16-Methyl-13,14-didehydro-;

16,16-Dimethyl-13,14-didehydro-;

16-Fluoro-13,14-didehydro-;

16,16-Difluoro-13,14-didehydro-;

17-Phenyl-18,19,20-trinor-13,14-didehydro-;

17-(m-trifluoromethylphenyl)- 18,19,20-trinor-13,14-didehydro-;

17-(m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-;

17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-;

16-Methyl-17-phenyl-18,19,20-trinor-13,14-didehydro:;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;

16-Fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;

16,16-Difluoro-17-phenyl- 18,19,20-trinor-13,14-didehydro-;

16-Phenoxy-17,18,19,20-tetranor-13,14-didehydro-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-didehydro-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-;

16-Phenoxy-18,19,20,-trinor-13,14-didehydro-;

16-Methyl-16-phenoxy-18,19,20 -trinor-13,14-didehydro-;

13,14-Dihydro-;

16-Methyl-13,14-dihydro-;

16,16-Dimethyl-13,14-dihydro-;

16-Fluoro-13,14-dihydro-;

16,16-Difluoro-13,14-dihydro-;

17-Phenyl-18,19,20-trinor-13,14-dihydro-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-;

17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;

17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;

16-Methyl-17-phenyl-18,19,20-trinor- 13,14-dihydro-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14 -dihydro-;

16-Fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16,16-Difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

16-Phenoxy-17,18,19,20-tetranor-13,14-dihydro-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-

16-phenoxy-18,19,20-trinor-13,14-dihydro-;

16-Methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-;

2,2-Difluoro-16-methyl-;

2,2-Difluoro-16,16-dimethyl-;

2,2-Difluoro-16-fluoro-;

2,2-Difluoro-16,16-difluoro-;

2,2-Difluoro-17-phenyl- 18,19,20-trinor-;

2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-;

2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-;

2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-;

2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-16-fluoro-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-;

2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-;

2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;

2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-;

2,2Difluoro-16-phenoxy-18,19,20-trinor-;

2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-;

2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-;

2,2-Difluoro-16-methyl-13,14-didehydro-;

2,2-Difluoro-16,16-dimethyl-13,14-didehydro-;

2,2-Difluoro-16-fluoro-13,14-didehydro-;

2,2-Difluoro-16,16-difluoro-13,14-didehydro-;

2,2-Difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;

2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-didehydro-;

2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-;

2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-;

2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;

2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;

2,2,16-Trifluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;

2,2,16,16-Tetrafluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;

2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-;

2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-didehydro-;

2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-;

2,2-Difluoro-16-phenoxy-18,19,20-trinor-13,14-didehydro-;

2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro;

2,2-Difluoro-13,14-dihydro-;

2,2-Difluoro-16-methyl-13,14-dihydro-;

2,2-Difluoro-16,16-dimethyl-13,14-dihydro-;

2,2,16-Trifluoro-13,14-dihydro-;

2,2,16,16-Tetrafluoro-13,14-dihydro-;

2,2-Difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,10-trinor-13,14-dihydro-;

2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2,16-Trifluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2,16,16-Tetrafluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-16-phenoxy -17,18,19,20-tetranor-13,14-dihydro-;

2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

2,2-Difluoro-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

16-Methyl-cis-13;

16,16-Dimethyl-cis-13-;

16-Fluoro-cis-13-;

16,16-Difluoro-cis-13-;

17-Phenyl-18,19,20-trinor-cis-13-;

17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-13-;

17-(m-chlorophenyl)-18,19,20-trinor-cis-13-;

17-(p-fluorophenyl)-18,19,20-trinor-cis-13-;

16-Methyl-17-phenyl-18,19,20-trinor-cis-13-;

16,16-Dimethyl-17-phenyl-18,19,20-trinor-cis-13-;

16-Fluoro-17-phenyl-18,19,20-trinor-cis-13-;

16,16-Difluoro-17-phenyl-18,19,20-trinor-cis-13-;

16-Phenoxy-17,18,19,20-tetranor-cis-13-;

16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-;

16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-13-;

16-(p-fluorophenoxy)-17,18,19,20-tetranor-cis-13-;

16-Phenoxy-18,19,20-trinor-cis-13-;

16-Methyl-16-phenoxy-18,19,20-trinor-cis-13-;

2,2-Difluoro-cis-13-;

2,2-Difluoro-16-methyl-cis-13-;

2,2-Difluoro-16,16-dimethyl-cis-13-;

2,2-Difluoro-16-fluoro-cis-13-;

2,2-Difluoro-16,16-difluoro-cis-13-;

2,2-Difluoro-17-phenyl-18,19,20-trinor-cis-13-;

2,2-Difluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-13-;

2,2-Difluoro-17-(m-chlorophenyl)-18,19,20-trinor-cis-13-;

2,2-Difluoro-17-(p-fluorophenyl)-18,19,20-trinor-cis-13-;

2,2-Difluoro-16-methyl-17-phenyl-18,19,20-trinor-cis-13-;

2,2-Difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-;

2,2-Difluoro-16-fluoro-17-phenyl-18,19,20-trinor-cis-13-;

2,2-Difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-cis-13-;

2,2-Difluoro-16-fluoro-18-phenyl-19,20-dinor-cis-13-;

2,2-Difluoro-16,16-difluoro-18-phenyl-19,20-dinor-cis-13-;

2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-;

2,2-Difluoro-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-;

2,2-Difluoro-16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-13-;

2,2-Difluoro-16-(p-fluorophenoxy)-17,18,19,20-tetranor-cis-13-;

2,2-Difluoro-16-phenoxy-18,19,20-trinor-cis-13-;

2,2-Difluoro-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-;

3-Oxa-;

3-Oxa-16-methyl-;

3-Oxa-16,16-dimethyl-;

3-Oxa-16-fluoro-;

3-Oxa-16,16-difluoro-;

3-Oxa-17-phenyl-18,19,20-trinor-;

3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-;

3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-;

3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-;

3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-;

3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-;

3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-;

3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-;

3Oxa-16-phenoxy-17,18,19,20-tetranor-;

3Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-;

3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-;

3-Oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor-;

3-Oxa-16-phenoxy-18,19,20-trinor-;

3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-;

3-Oxa-13,14-didehydro-;

3-Oxa-16-methyl-13,14-didehydro-;

3-Oxa-16,16-dimethyl-13,14-didehydro-;

3-Oxa-16-fluoro-13,14-didehydro-;

3-Oxa-16,16-difluoro-13,14-didehydro-;

3-Oxa-17-phenyl-18,19,20-trinor-13,14-didehydro-;

3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-didehydro-;

3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-didehydro-;

3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-didehydro-;

3Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;

3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-;

3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;

3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-;

3-Oxa-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-;

3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-didehydro-;

3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-didehydro-;

3-Oxa-16-phenoxy-18,19,20-trinor-13,14-didehydro-;

3-Oxa-16-methyl-16 -phenoxy-18,19,20-trinor-13,14-didehydro-;

3-Oxa-13,14-dihydro-;

3-Oxa-16-methyl-13,14-dihydro-;

3-Oxa-16,16-dimethyl-13,14-dihydro-;

3-Oxa-16-fluoro-13,14-dihydro-;

3-Oxa-16,16-difluoro-13,14-dihydro-;

3-Oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-;

3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-13,14-dihydro-;

3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-;

3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-;

3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14 -dihydro-;

3-Oxa-16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-;

3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-;

3-Oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-;

3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

3-Oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-;

3-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-;

3-Oxa-cis-13-;

3-Oxa-16-methyl-cis-13-;

3-Oxa-16,16-dimethyl-cis-13-;

3-Oxa-16-fluoro-cis-13-;

3-Oxa-16,16-difluoro-cis-13-;

3-Oxa-17-phenyl-18,19,20-trinor-cis-13-;

3-Oxa-17-(m-trifluoromethylphenyl)-18,19,20-trinor-cis-13-;

3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-cis-13-;

3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-cis-13-;

3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-cis-13-;

3-Oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-;

3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-cis-13-;

3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-cis-13-;

3-Oxa-16-phenoxy-17,18,19,20-tetranor-cis-13-;

3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-;

3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-cis-13-;

3-Oxa-(p-fluorophenoxy)-17,18,19,20-tetranor-cis-13-;

3-Oxa-16-phenoxy-18,19,20-trinor-cis-13-;

3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-;

3-Oxa-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16-methyl-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16,16-dimethyl-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16-fluoro-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16,16-difluoro-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-17-(m-trifluromethylphenyl)-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-17-(m-chlorophenyl)-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-17-(p-fluorophenyl)-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16,16-Dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-trans-14,15-dihydro-;

3-Oxa-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-trans-14,15-didehydro-;

3-Oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-;and

3-Oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-.

Likewise following the procedures of Preparations 1, 2, and 3 asdescribed above, but employing corresponding starting materials, thereare prepared the

formula-VII 9-deoxy-6,9-epoxy-5-iodo-PGF₁α -type compounds,

formula-III 6-keto-PGF₁α -type compounds, and

formula-XX 9-deoxy-6,9-epoxy-6-hydroxy-PGF₁α -type compounds

having the following structural features:

2,3-Didehydro-;

2,2-Dimethyl-;

2a,2b-Dihomo-;

4-Oxa-4a-homo-;

7a-Homo-;

11β-;

11-Deoxy-;

11-Deoxy-11-methylene-;

11-Deoxy-11-hydroxymethyl-;

15β-;

15-Keto-;

15-Deoxy-;

15-Methyl-15(S)-;

15-methyl-15(R)-; and

17,18-Didehydro-.

PREPARATION 4

5ξ-iodo-9-deoxy-6,9-epoxy-PGF₁α, p-Phenylphenacyl Ester (Formula VII).

A mixture of the formula-VII iodo acid compound (Preparation 3, FormulaVII, 0.20 g.), p-phenylphenacyl bromide (0.50 g.), 0.4 ml. ofdiisopropylethylamine, and 10 ml. of acetonitrile is stirred at about25° C. for 40 min. It is mixed with dilute aqueous citric acid and brineand extracted with ethyl acetate. The organic phase is dried andconcentrated. The residue is subjected to silica gel chromatography,eluting with ethyl acetate (25-100%)-Skellysolve B to yield the title5-iodo compound as a colorless oil, 0.20 g.

PREPARATION 5

2-decarboxy-2-azidomethyl-PGF₂α, or 2-nor-PGF₂α, azide (Formula CV: Z₁is --CH═CH--(CH₂)₃ -- or --CH═CH--(CH₂)₂ --, respectively, R₃₁ ishydroxy, Y₁ is trans-CH═CH--, R₃₄ and R₃₅ of the L₁ moiety and R₃₃ ofthe M₁ moiety are all hydrogen, and R₃₀ is n-butyl).

A. To a cold solution (0° C.) of PGF₂α (7.1 g.), 125 ml. of acetone, 10ml. of water, and 2.2 g. of triethylamine is added with stirring 3.01 g.of isobutylchloroformate. The mixture is stirred at 0° C. for about 30min. at which time a cold solution of 7 g. of sodium azide on 35 ml. ofwater is added. The mixture is then stirred at 0° C. for one hr. atwhich time it is diluted with 300 ml. of water and extracted withdiethyl ether. The organic layers are then combined; washed with water,dilute carbonate solution, saturated saline; dried; and concentratedunder reduced pressure, maintaining bath temperature below 30° C., toyield 2-nor-PGF₂α, azide.

B. 2-Decarboxy-2-azidomethyl-PGF₂α is prepared by the following reactionsequence:

(1) A solution of t-butyldimethylsilyl chloride (10 g.), imidazole (9.14g.), and PGF₂α (3 g.) in 12 ml. of dimethylformamide are magneticallystirred under nitrogen atmosphere for 24 hr. The resulting mixture isthen cooled in an ice bath and the reaction quenched by addition of icewater. The resulting mixture is then diluted with 150 ml. of water andextracted with diethyl ether. The combined ethereal extracts are thenwashed with water, saturated ammonium chloride, a sodium chloridesolution, and thereafter dried over sodium sulfate. Solvent is removedunder vacuum yielding PGF₂α, t-butyldimethylsilyl ester,9,11,15-tris-(t-butyldimethylsilyl ether). NMR absorptions are observedat 0.20, 0.30, 0.83, 0.87, 0.89, 1.07-2.50, 3.10- 4.21, and 5.38 δ.Characteristic infrared absorptions are observed at 970, 1000, 1060,1250, 1355, 1460, 1720, and 2950 cm⁻¹.

(2) To a magnetically stirred suspension of lithium aluminum hydride(7.75 g.) in 18 ml. of diethyl ether is added dropwise at roomtemperature over a period of 12 min. 8.71 g. of the reaction product ofpart (1) above in 40 ml. of diethyl ether. After stirring at ambienttemperature for one hr., the resulting product is cooled in an ice waterbath and saturated sodium sulfate is added dropwise until the appearanceof a milky suspension. The resulting product is coagulated with sodiumsulfate, triturated with diethyl ether, and the solvent is removed bysuction filtration. Concentration of the diethyl ether under vacuumyields 7.014 g. of 2-decarboxy-2-hydroxymethyl-PGF₂α,9,11,15-tris-(t-butyldimethylsilyl ether), NMR absorptions are observedat 0.03, 0.82, 0.87, 1.10-2.60, 3.30-4.30, and 5.37 δ. Characteristicinfrared absorptions are observed at 775, 840, 970, 1065, 1250, 1460,2895, 2995, and 3350 cm⁻¹.

(3) p-Toluenesulfonyl chloride (3.514 g.), pyridine (44 ml.), and thereaction product of subpart (2), 7.014 g., are placed in a freezer at-20° C. for 3 days. Thereafter, 7.200 g. of2-decarboxy-2-p-toluenesulfonyloxymethyl-PGF₂α,9,11,15-tris-(t-butyldimethylsilyl ether), is recovered. NMR absorptionsare observed at 0.10, 0.94, 0.97, 1.10, 2.50, 4.03, 3.80-4.80, 5.45,7.35, and 7.80 δ. Infrared absorptions are observed at 775, 970, 1180,1190, 1250, 1360, 1470, 2900, and 2995 cm⁻¹.

(4) The reaction product of subpart (3) (2.13 g.) is placed in 42 ml. ofacetic acid, tetrahydrofuran, and water (3:1:1) containing 0.25 ml. of10 percent aqueous hydrochloric acid. The reaction mixture becomeshomogeneous after vigorous stirring for 16 hr. at room temperature. Theresulting solution is then diluted with 500 ml. of ethyl acetate; washedwith saturated sodium chloride and ethyl acteate; dried over sodiumsulfate; and evaporated under reduced pressure, yielding 1.301 g. of anoil. Crude product is chromatographed on 150 g. of silica gel packedwith ethyl acetate. Eluting with ethyl acetate yields 0.953 g. of2-decarboxy-2-p-toluenesulfonyloxymethyl-PGF₂α.

(5) The reaction product of subpart (4), (0.500 g.) in 5.0 ml. ofdimethylformamide was added to a stirred suspension of sodium azide (1.5g.) in 20 ml. of dimethylformamide. Stirring is continued at ambienttemperature for 3 hr. The reaction mixture is then diluted with water(75 ml.), extracted with diethyl ether (500 ml.), and the etheralextracts washed successively with water, saturated sodium chloride, anddried over sodium sulfate. Removal of the diethyl ether under reducedpressure yields 0.364 g. of 2-decarboxy-2-azidomethyl-PGF₂α. Acharacteristic azido infrared absorption is observed at 2110 cm⁻¹.

PREPARATION 6

2-decarboxy-2-aminomethyl-PGF₂α (Formula CXXV: Z₁ is cis-CH═CH--(CH₂)₃--, R₃₁ is hydroxy, Y₁ is trans-CH═CH--, R₃₄ and R₃₅ of the L₁ moietyand R₃₃ of the M₁ moiety are all hydrogen, and R₃₀ is n-butyl).

Crude 2-decarboxy-2-azidomethyl-PGF₂α (Prep. 5, 0.364 g.) in 12 ml. ofdiethyl ether is added to a magnetically stirred suspension of lithiumaluminum hydride (0.380 g.) in 20 ml. of diethyl ether. Reactiontemperature is maintained at about 0° C. and addition of lithiumaluminum hydride proceeds dropwise over a 4 min. period. After additonis complete, the resulting mixture is stirred at ambient temperature for1.5 hr. and thereafter placed in an ice bath (0°-5° C.). Excess reducingagent is then destroyed by addition of saturated sodium sulfate. Aftercessation of gas evolution, the resulting product is coagulated withsodium sulfate, triturated with diethyl ether, and solid salts removedby filtration. The filtrate is then dried with sodium sulfate, andevaporated under reduced pressure to yield 0.304 g. of a slightly yellowoil. This oil (100 mg.) is then purified by preparative thin layerchromatography, yielding 42 g. of title product. NMR absorptions areobserved at 0.90, 1.10-2.80, 3.28, 3.65-4.25, and 5.45 δ. Characteristicinfrared absorptions are observed at 970, 1060, 1460, 2995, and 3400cm⁻¹. The mass spectrum shows parent peak at 699.4786 and other peaks at6.28, 684, 595, 217, and 274.

PREPARATION 7

5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, Amide, less polar and more polarisomers (Formula VII: D is --(CH₂)₃ --, Q is ##STR108## R₄ is n-pentyl,R₁₈ is ##STR109## R₁₉ is ##STR110## R₃₇ is iodo and X istrans--CH═CH--).

A solution of the formula-VII iodo-ether acid, mixed isomers(Preparation 3, 5.0 g.) in 50 ml. of acetone is cooled to about -10° C.and treated with 3.0 ml. of triethylamine and 3.0 ml. of isobutylchloroformate. After 5 min. there is added 100 ml. of acetonitrilesaturated with ammonia, and the reaction mixture allowed to warm toabout 25° C. The mixture is filtered, and the filtrate concentrated. Theresidue is taken up in ethyl acetate and water. The organic phase iswashed with water, dried over magnesium sulfate and concentrated. Theresidue is subjected to silica gel chromatography, eluting with acetone(25-100%)-methylene chloride. There are obtained the formula-VIIiodo-ether, amide, less polar isomer, 0.02 g., having R_(f) 0.40 (TLC onsilica gel in acetone); a fraction of mixed less and more polar isomers,2.2 g.; and the more polar isomer, 1.5 g., having R_(f) 0.37 (TLC onsilica gel in acetone), infrared absorption at 3250, 3150, 1660, 1610,1085, 1065, 1050, and 965 cm⁻¹, and NMR peaks at 6.4, 5.5, 3.5-4.7 and0.9 δ.

PREPARATION 8

5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, Methylamide, mixed isomers (FormulaVII: R₁₉ is ##STR111##

A solution of the formula-VII 5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, mixedisomers (Preparation 3, 4.66 g.) in 50 ml. of acetone is treated with1.42 ml. of triethylamine and cooled to -5° C. Thereupon 1.3 ml. ofisobutyl chloroformate is added, with stirring at 0° C. for 5 min.,followed by 25 ml. of 3 M methylamine in acetonitrile. The solution isstirred for 20 min. more as it warmed to about 25° C. The mixture isfiltered and concentrated. The oily residue is triturated with methylenechloride, and filtered to remove a precipitate. The filtrate issubjected to silica gel chromatography, eluting with acetone(50-90%)-methylene chloride, to yield the5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, methylamide mixed isomers, 3.45 g.,having NMR peaks at 6.3, 5.4-5.7, 3.2-4.7, 2.78, and 0.7-2.65 δ.

PREPARATION 9

5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, n-Butylamide, Mixed Isomers (Formula:VII: R₁₉ is ##STR112##

A solution of the formula-VII iodo-ether acid, mixed isomers(Preparation 3, 5.0 g.) in 50 ml. of acetone is cooled to about -10° C.and treated with 2.0 ml. of triethylamine and 1.9 ml. of isobutylchloroformate. After 6 min. there is added a solution of 15 ml. ofn-butylamine in 20 ml. of acetone. After about 15 min. the reactionmixture is allowed to warm to about 25° C. and stirred for 3 hr. Themixture is concentrated and the residue is taken up in ethyl acetate.The solution is washed with water and brine, dried over magnesiumsulfate, and concentrated. The residue is chromatographed on silica gel,eluting with acetone (5-100%)-methylene chloride to yield the titlecompounds, 5.3 g. The product is rechromatographed to remove color usingsilica gel and eluting with acetone-methylene chloride (1:3). From 0.48g. there is obtained the title compounds as a pale yellow oil, 0.35 g.,having R_(f) 0.63 (TLC on silica gel in acetone), and infraredabsorption peaks at 3300, 3100, 1735, 1715, 1645, 1555, 1070, 1055,1020, and 965 cm⁻¹.

PREPARATION 10

6keto-PGF₁α, n-Butylamide

I. There is first prepared (5Z)-9-deoxy-6,9α-epoxy-Δ⁵ -PGF₁,n-butylamide. A solution of 5ξ-iodo-6ξ,9α-epoxy-PGF₁, n-butylamide(Preparation 9, 3.5 g.) in 100 ml. of benzene is treated with 8 ml. ofDBN at 40°-45° C. for about 16 hr. The mixture is cooled, diluted withice water, and extracted with chloroform, keeping a few drops oftriethylamine in the organic phase. The combined organic phases arewashed with ice water, dried and concentrated to an oil, 3.64 g. Ofthis, 3.1 g. is taken up in warm diethyl ether, and the ether solutionwhen cooled yields 1.5 g., mainly solid. The product is recrystallizedfrom ether, 0.85 g., m.p. 102°-104° C.

II. A solution of the above (5Z)-9-deoxy-6,9α-epoxy-Δ⁵ -PGF₂,n-butylamide (3.0 g.) in 25 ml. of tetrahydrofuran is treated withsufficient 10% aqueous potassium hydrogen sulfate solution to bring thepH to 5.0. The mixture is concentrated to remove tetrahydrofuran and theresidue is taken up in water and ethyl acetate. Sodium chloride is addedto saturation and the organic phase is separated. The aqueous phase isextracted with acetone-ethyl acetate (1:4) and the organic phases arecombined. The organic phases are washed with brine, dried, andconcentrated. The residue, 2.10 g., is chromatographed on silica gel,eluting with acetone (33-100%)-methylene chloride to yield a 1:1 mixtureof the title compound together with the corresponding9-deoxy-6,9α-epoxy-6-hydroxy compound, having R_(f) 0.57 (TLC on silicagel in acetone). The mixture is dissolved in 10 ml. of tetrahydrofuranand acidified with aqueous potassium hydrogen sulfate, therebyconverting the mixture to substantially all 6-keto-PGF₁α, n-butylamide,having R_(f) 0.58 (TLC on silica gel in acetone). The product isrecovered by concentrating the solution, portioning between ethylacetate and water, washing the organic phase with brine, andconcentrating to an oil, 1.90 g., having a high resolution mass spectralpeak (TMS derivative) at 641.4258.

PREPARATION 11

5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, Benzylamide, mixed isomers (FormulaVII: R₁₉ is ##STR113##

Following the procedures of Preparation 8, there are used 4.66 g. of theformula-VII 5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, mixed isomers, and 1.08 g.of benzylamine instead of methylamine. The crude product ischromatographed on silica gel, eluting with acetone (50-70%)-methylenechloride, to yield the 5ξ-iodo-9-deoxy-6ξ-9α-epoxy-PGF₁, benzylamidemixed isomers, 4.1 g., having NMR peaks at 7.3, 6.6, 5.3-5.7, and3.5-4.6 δ.

PREPARATION 12

5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, Anilide, mixed isomers (Formula VIIR₁₉ is ##STR114##

Following the procedures of Preparation 8, there are used 4.66 g. of theformula-VII 5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, mixed isomers, and 0.94 g.of aniline. The crude product is chromatographed on silica gel, elutingwith acetone (10-50%)-methylene chloride, to yield the5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, anilide mixed isomers, 4.0 g., havingNMR peaks at 8.4, 6.9-7.7, 5.3-5.7, and 3.4-4.7 δ.

EXAMPLE 1

6-keto-PGE₁, Methyl Ester (Formula VI: D is --(CH₂)₃ --, Q is ##STR115##R₄ is n-pentyl, ##STR116## is ##STR117## R₁₉ is --COOCH₃, and X istrans-CH═CH--).

A. Refer to Chart A. A solution of formula-III 6-Keto-PGF₁α, methylester (0.50 g.) in 25 ml. of methylene chloride is treated with 3 ml. ofdihydropyran and 3 ml. of a saturated solution of pyridine hydrochloridein methylene chloride and left standing about 5 hr. at about 25° C. oruntil TLC shows that the starting material has disappeared, and that thebis(tetrahydropyranyl)ether has been formed, having R_(f) 0.22 (TLC onsilica gel in acetone-methylene chloride (1:9)) or R_(f) 0.47 (TLC onsilica gel in acetone-methylene chloride (1:3)). The reaction mixture isconcentrated, washed with aqueous sodium bicarbonate and brine, dried,and concentrated. The residue is subjected to silica gel chromatography,eluting with acetone (10-25%) in methylene chloride to yield theformula-IV bis(tetrahydropyranyl)ether, methyl ester, having infraredpeaks at 3500, 1745, 1730, 1200, 160, 1130, 1110, 1075, 1035, 1020, 980,915, 870, 815, and and 735 cm⁻¹ ; mass spectral lines (TMS) at 552, 522,366, 348, 331, 330, 304, and 85; and NMR spectral peaks at 5.5, 4.67,3.65, 3.2-3.7, and 0.9 δ.

B. The reaction product from part A, containing 6-keto-PGF₁α,bis(tetrahydropyranyl)ether, methyl ester corresponding to formula IV,is oxidized to compound V. A composite from several lots, weighing 0.93g., in 20 ml. of acetone is treated at -10° C. with 2.0 ml. of Jonesreagent. After stirring for 1.5 hr. the reaction mixture is quenchedwith isopropanol and extracted with diethyl ether. The extract is washedwith brine, dried, and concentrated. The residue is subjected to silicagel chromatography, eluting with ethyl acetate (20-50%)-Skellysolve B toyield the formula-V 6-keto-PGF₁, bis(tetrahydropyranyl)ether, methylester, 0.52 g., having R_(f) 0.52 (TLC on silica gel in ethylacetate-Skellysolve B (1:1)); and infrared peaks at 1745 and 1725 cm⁻¹(free of OH at 3000-3500).

C. The product of part B is hydrolyzed in 3 ml. of acetic acid and 1.5ml. of water at 40° C. for 3 hr., then mixed with brine and extractedwith chloroform. The organic phase is washed with brine, dried, andconcentrated. The residue is subjected to silica gel chromatographyeluting with ethyl acetate (25-100%)-Skellysolve B to yield 0.15 g. ofthe title compound, having infrared peaks at 3380, 1750, 1710, 1250,1200, 1180, 1105, 1070, and 975 cm⁻¹, and mass spectral lines (TMS) at526.3123, 511, 508, 495, 455, 436, 382, 313.2004, and 199. An analyticalsample, recrystallized as needles from diethyl ether-hexane, m. 39°-40°C., has R_(f) 0.33 (TLC on silica gel in ethyl acetate).

EXAMPLE 2

6-keto-PGE₁ (Formula VI: D is --(CH₂)₃ --,

Q is ##STR118## R₄ is n-pentyl, ##STR119## is ##STR120## R₁₉ is --COOH,and X is trans-CH═CH--).

A. Refer to Chart B. There is first prepared the formula-VIIIbis(tetrahydropyranyl)ether of 9-deoxy-6,9-epoxy-5-iodo-PGF₁α, methylester. The formula-VII product of Preparation 1 (2.0 g.) in 20 ml. ofmethylene chloride, together with 4 ml. of dihydropyran and 1 ml. of asaturated solution of pyridine hydrochloride in methylene chloride, isleft standing 16 hr. at about 25° C. The mixture is washed with aqueoussodium bicarbonate and brine, dried and concentrated to a colorless oil.The residue is subjected to silica gel chromatography, eluting withacetone (10%)-methylene dichloride, to yield about 3.0 g. having R_(f)0.73 (TLC on silica gel in ethyl acetate); and infrared peaks at 1765,1215, 1140, 1085, 1045, 1036, 985, 875, 820, and 740 cm⁻¹ (free of OH at3000-3500).

B. The formula-IV 6-keto PGF-type compound is prepared in several stepsas follows. The product of part A above (about 3.0 g.) is mixed with 100ml. of benzene and 4 ml. of 1,5-diazabicyclo[4.3.0]nonene-5 (DBN) andheld at 40° C. for 4 hr., then at about 25° C. for 64 hr. The mixture iswashed with ice-water, dried over magnesium sulfate, and concentrated tothe enol ether, 9-deoxy-6,9-epoxy-Δ⁵ -PGF₁α,bis(tetrahydropyranyl)ether, methyl ester, 2.5 g. having NMR peaks at5.55, 4.5-5.1, 3.2-4.5, and 0.9 δ, and infrared peaks at 1740, 1695,1200, 1165, 1130, 1075, 1035, 1020, 975, and 870 cm⁻¹.

The enol ether (2.25 g.) is dissolved in 25 ml. of diethyl ether, mixedwith 10 ml. of a dilute aqueous solution of potassium hydrogen sulfateand stirred at about 25° C. The reaction is monitored by TLC (silica gelplates in acetone (10%)-methylene chloride) as a more polar material isslowly formed. After several hours 50 ml. of tetrahydrofuran is addedand stirring continued. The mixture is concentrated and the residue isextracted with ethyl acetate. The extract is washed with brine, dried,and concentrated to an oil. The residue is subjected to silica gelchromatography eluting with acetone (10-25%)-methylene chloride to yieldthe formula-IV 6-keto-PGF₁α, bis(tetrahydropyranyl)ether, methyl ester,1.91 g., having R_(f) 0.22 (TLC on silica gel in acetone (10%)-methylenechloride), having the same infrared spectrum as the correspondingformula-IV intermediate of Example 1.

C. The acid form of the product of part B is prepared by saponifyingthat product. The methyl ester of part B (0.75 g.) in 25 ml. methanoland 7 ml. of 3 N. sodium hydroxide is stirred at about 25° C. for 3 hr.The mixture is chilled, saturated with sodium chloride, acidified withpotassium hydrogen sulfate, and extracted with ethyl acetate. Theextract is washed with brine, dried, and concentrated to an oil, 0.68g., having R_(f) 0.61 (TLC on silica gel in A-IX solvent).

D. The formula-V 6-keto PGE-type compound is obtained as follows. Theproduct of part C (0.68 g.) in 50 ml. of acetone is cooled to -15° C.and treated with 2 ml. of Jones reagent added slowly with stirring.Stirring is continued at about the same temperature for one hr., then at-5° C. for 0.5 hr. The reaction is quenched with isopropanol and themixture concentrated to about half volume. Brine is added and themixture extracted with diethyl ether. The extract is washed with brine,dried, and concentrated to a yellow oil, 0.61 g., having R_(f) 0.64 (TLCon silica gel in A-IX). After silica gel chromatography a fraction isobtained, 0.31 g.

E. The formula-VI title compound is finally obtained on hydrolysis ofthe blocking groups. The product of part D (0.31 g.) is treated in 7 ml.of acetic acid and 3 ml. of water at 40° C. for one hr. and a further 16hr. at about 25° C. Brine is added and the mixture is extracted withchloroform. The extract is washed with water, dried, and concentrated toan oil, 0.25 g. This product is subjected to silica gel chromatography,eluting with ethyl acetate (25-100%)-hexane to obtain the titlecompound, 0.065 g. having NMR peaks at 5.72, 5.57, 3.8-4.3, 2.1-2.8, and0.9 δ; and infrared absorption peaks at 3420, 3000, 2800, 1755, 1740,1710, 1315, 1255, 1190, 1160, 1110, 1065, and 970. An analytical sampleis obtained as needles on recrystallizing from diethyl ether-hexane, m.67°-69° C.

Following the procedures of Example 2, but replacing the preparation ofthe formula-IV 6-keto PGF-type compound in part B with a preparationusing silver carbonate and perchloric acid, the same end product isobtained. Thus, instead of part B, the product of part A (2.5 g.) ismixed with 80 ml. of tetrahydrofuran, silver carbonate (one gram) and 7drops of 70% perchloric acid. The mixture is stirred vigorously at about25° C. for 22 hr. Additional perchloric acid (3 drops) is added andstirring continued for 4 hr. The mixture is filtered, the filtratetreated with brine and sodium carbonate, and extracted with ethylacetate. The extract is washed with brine, dried, and concentrated to anoil, 2.6 g. Silica gel chromatography, eluting with acetone(10-40%)-methylene chloride, yields the formula-IV 6-keto-PGF₁α,bis(tetrahydropyranyl)ether, methyl ester, an oil, 0.52 g. having R_(f)0.35 (TLC on silica gel in ethyl acetate-cyclohexane (1:1)). Thereafterthe 6-keto-PGE₁ product is obtained following parts C, D, and E above.

Following the procedures of Example 1 and 2 and Chart B but replacingthe formula-VII starting material with the appropriate formula-VIIcompounds obtained following Preparations 1, 2, and 3, there areobtained formula-VI compounds as follows:

2,2-Difluoro-6-keto-PGE₁, Methyl Ester

(15S)-15-Methyl-6-keto-PGE₁

(15r)-15-methyl-6-keto-PGE₁

16,16-dimethyl-6-keto-PGE₁

2,2-difluoro-16,16-dimethyl-6-keto-PGE₁, methyl ester

2,2-Difluoro-(15S)-15-methyl-6-keto-PGE_(1`), methyl ester

16-Phenoxy-17,18,19,20-tetranor-6-keto-PGE₁

16-phenyl-17,18,19,20-Tetranor-6-keto-PGE₁

17-phenyl-18,19,20-trinor-6-keto-PGE₁

2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-6-keto-PGE₁, methyl ester

13,14-Dihydro-6-keto-PGE₁

2,2-difluoro-13,14-dihydro-6-keto-PGE₁, methyl ester

2,2-Difluoro-13,14-didehydro-6-keto-PGE₁, methyl ester.

EXAMPLE 3

6-keto-13,14-didehyro-PGF₁α, 11,15-bis(tetrahydropyranyl)ether (FormulaXVIII: D₁ is --(CH₂)₃ --, Q₃ is ##STR121## wherein THP istetrahydropyranyl, R₂₃ is --COOH, R₂₆ is n-pentyl, R₃₆

is ##STR122## and X is --C.tbd.C--) and5ξ-Bromo-9-deoxy-6ξ,9-epoxy-14-bromo-15-keto-PGF₁α, Methyl Ester.

A. Refer to Chart C. The 5ξ,6ξ,14-tribromo-15-keto-PGF₁α, methyl ester(XII) is first prepared. A solution of 15-oxo-PGF₂α, methyl ester (U.S.Pat. No. 3,728,382, 3.38 g.) in about 25 ml. of pyridine is treateddropwise with a solution of pyridinium hydrobromide perbromide (7.08 g.)in 35 ml. of pyridine over 2.25 hr. Thereafter the mixture is stirredfor 27 hr., diluted with ether and filtered. The filtrate is washed withwater, cold hydrobromic acid (5%) aqueous sodium bicarbonate (5%), thendried and concentrated to yield 3.72 g. product. Similarly an additional1.06 g. is prepared and combined. The product is subjected to silica gelchromatography eluting with hexane-ethyl acetate (65:35) to yield XII,2.83 g., having NMR peaks at 0.90, 1.1-2.58, 2.58-3.4, 3.4-3.88, 3.67,3.88-4.61, 6.96, and 7.03 δ; infrared peaks at 3400, 1730, 1685, 1610,1245, 1200, 1170, 1085, and 1050 cm⁻¹ ; and mass spectral peaks (TMS) at746.0562, 636, 634, 632, 630, 555, 553, and 551.

There is also obtained, as a separate fraction from the chromatographyof the reaction product,5ξ-bromo-9-deoxy-6ξ,9-epoxy-14-bromo-15-keto-PGF₁α, methyl ester, 0.93g., having NMR peaks at 0.90, 1.10-3.03, 3.03-3.46, 3.65, 3.78-5.0, 6.91and 7.00 δ; infrared peaks at 3480, 2880, 2810, 1735, 1690, 1615, 1245,1200, 1175, 1150, and 1080 cm⁻¹ ; and mass spectral peaks (TMS) at594.099, 515, and 478.

B. 5ξ, 6ξ, 14-Tribromo-PGF₁α, methyl ester (XIII). A solution of XII(2.38 g.) in 20 ml. of methanol is added to a solution of sodiumborohydride (1.28 g.) in 40 ml. of methanol at -35° C. The temperatureis held at -25° C. for 1 hr. The mixture is diluted with diethyl etherand quenched with acetic acid. The solution is washed with salinesolution (5%) and aqueous bicarbonate (5%) solutions, dried, andconcentrated to a mixture of C-15 epimers (XIII). Separation is achievedby silica gel chromatography eluting with hexane-ethyl acetate (3:2followed by 1:1) to yield, first, the 15R epimer (XIII-15β), 1.57 g.having NMR peaks at 0.9, 1.1-3.35, 3.35-4.65, 3.66, and 5.75-6.21 δ;infrared peaks at 3380, 1735, 1725, 1250, 1200, 1175, 1075, and 1050cm⁻¹ ; high resolution mass spectral peak (TMS derivative) at 749.0362,and [α]_(D) - 11° in ethanol; and second, the 15S epimer (XIII-15α)0.605 g. having NMR peaks at 0.9, 1.10-3.35, 3.35-4.6, 3.66, and5.65-6.15 δ; infrared peaks at 3380, 1740, 1650, 1435, 1250, 1200, 1175,1120, 1080, and 1045 cm⁻¹ ; high resolution mass spectral peak (TMSderivative) at 749.0384; and [α]_(D) -4° in ethanol.

C. 14-Bromo-PGF₂α, methyl ester (XIV). A solution of XIII-15α (0.60 g.)in 20 ml. of methanol is treated with ammonium chloride (0.11 g.) andzinc dust (0.28 g.). The mixture is stirred for 1.5 hr., diluted withbenzene and filtered. The filtrate is washed with 0.2 M. potassium acidsulfate, dried, and concentrated to yield 0.37 g., having R_(f) 0.26(TLC on silver nitrate-treated silica gel in ethyl acetate); NMR peaksat 0.88, 1.1-2.71, 2.71-3.55, 3.66, 3.80-4.35, 5.23-5.56 and 5.84 δ; andinfrared peaks at 3320, 2900, 2820, 1940, 1650, 1430, 1310, 1240, 1215,1170, 1115, and 1030 cm⁻¹.

D. 5ξ-Iodo-9-deoxy-6ξ,9-epoxy-14-bromo-PGF₁α, methyl ester (XV). Asolution of XIV (1.9 g.) in 30 ml. of methylene chloride is added to asuspension of iodine (2.85 g.) potassium iodide (1.88 g.) sodium acetate(0.92 g.) and water (6 ml.). The mixture is stirred for 2 hr., treatedwith 20 ml. of 2 N. sodium thiosulfate, washed with aqueous 5% salinesolution, dried and concentrated to yield XV, 2.95 g. An analyticalsample obtained by subjecting a portion to silica gel chromatography hadNMR peaks at 0.89, 1.1-3.18, 3.66, 3.6-4.8, and 5.88 δ; mass spectralpeaks (TMS) at 701.1183, 645, 637, 589, 547, 529, 510, and 173; andinfrared spectral peaks at 3380, 1740, 1655, 1230, 1170, 1080, and 1050cm⁻¹.

E. 5ξ-Iodo-9-deoxy-6ξ,9-epoxy-14-bromo-PGF₁α,11,15-bis(tetrahydropyranyl)ether, methyl ester (XVI). A solution of XV(1.0 g.) in 10 ml. of methylene chloride is treated with dihydropyran (3ml.) and 3 ml. of a saturated solution of pyridine hydrochloride inmethylene chloride. After 20 hr. the mixture is diluted with diethylether, washed with aqueous sodium bicarbonate (5%) and saline solution(5%), dried, and concentrated. The residue is 1.12 g., having NMR peaksat 0.9, 1.05-2.20, 2.2-3.2, 3.2-4.35, 3.66, 4.35-4.15, and 5.7-6.1 δ;and infrared peaks at 2900, 2820, 1760, 1440, 1350, 1210, 1125, 1090,1035, 1025, 970, and 910 cm⁻¹.

F. 6-Keto-13,14-didehydro-PGF₁α, 11,15-bis(tetrahydropyranyl)ether(XVII). A solution of XVI (1.1 g.) in 15 ml. of dimethyl sulfoxide and1.5 ml. of methanol is treated with potassium t-butoxide (0.504 g.) for20 hr. The mixture is diluted with 60 ml. of water, cooled, acidifiedwith 5% phosphoric acid, and extracted with diethyl ether. The organicphase is washed with brine, dried, and concentrated to an oil, 0.81 g.,which is subjected to silica gel chromatography, eluting withhexane-ethyl acetate (7.5:2.5) to yield the title compound, 0.313 g.,having NMR peaks at 0.9, 1.1-3.0, 3.05-5.1, and 6.5-7.5 δ; and infraredpeaks at 3300, 3900, 2810, 2500-2700, 2225, 1740, 1710, 1430-1460, 1190,1130, 1120, 1075, 1035, 1015, 975, and 905 cm⁻¹.

EXAMPLE 4

6-keto-13,14-didehydro-PGE₁ (Formula VI: D is --(CH₂)₃ --, Q is##STR123## R₄ is n-pentyl, ##STR124## is ##STR125## R₁₉ is --COOH, and Xis --C.tbd.C--).

Refer to Chart A. A solution of the formula-IV6-keto-13,14-didehydro-PGF₁α, 11,15-bis(tetrahydropyranyl)ether (Example3, 1.1 g.) in 12 ml. of acetone is treated at -10° C. with 2.67 M. Jonesreagent added dropwise in three 1 ml. aliquots at 15 min. intervals. Themixture is quenched with isopropanol added dropwise, diluted withdiethyl ether, and partitioned with 5% aqueous sodium chloride, dried,and concentrated. The residue consists of the formula-Vbis(tetrahydropyranyl)ether of the title compound, 0.26 g., having R_(f)0.29 (TLC on silica gel in A-IX-cyclohexane (1:1)).

The product above is hydrolyzed in a mixture of acetic acid (15 ml.),water (7.5 ml.) and tetrahydrofuran (1.0 ml.) for 4.5 hr. at about 40°C., then diluted with 30 ml. of water and lyophilized to a yellow oil,0.14 g. The oil is subjected to silica gel chromatography, eluting withhexaneethyl acetate (3:2), to yield the title compound, 0.048 g., havingNMR peaks at 0.90, 1.1-2.05, 2.05-3.33, 4.03-4.70, and 5.5-6.3 δ; massspectral peaks (TLC) at 582.3210, 567, 511, 492, 477, 436, 421, 410,402, 387, 291.1768, 173, and 111; and infrared peaks at 3350, 2870,2500-2600, 2810, 2240, 1740, 1710, 1450, 1400, 1155, and 1080 cm⁻¹.

EXAMPLE 5

6-keto-13,14-didehydro-PGF₁α (Formula III: D is --(CH₂)₃ --, Q is##STR126## R₄ is n-pentyl, R₁₈ is ##STR127## R₁₉ is --COOH, and X is--C.tbd.C--).

A solution of the 5ξ-iodo-9-deoxy-6ξ,9-epoxy-14-bromo-PGF₁α, methylester (Example 3D, 1.67 g.) in 30 ml. of dimethyl sulfoxide is treatedwith potassium tertbutoxide (1.63 g.) in 3 ml of methanol at about 25°C. for 23 hr., then diluted with water (6 ml.) and reacted for a further3 hr. The mixture is diluted with ether and partitioned with cold 3.5%phosphoric acid. The organic phase is washed with 5% sodium chloridesolution, dried, and concentrated. The residue (0.87 g.) is subjected tosilica gel chromatography eluting with hexane-ethyl acetate (1:1) toyield the formula-III title compound, 0.59 g., having NMR peaks at 0.90,1.1-3.5, 3.7-5.2, and 5.28-6.51 δ; mass spectral peak (TMS derivative)at 670.3836; and infrared absorption peaks at 3360, 2670, 2230, 1710,1320, 1245, 1205, 1145, 1115, 1090, 1055, and 995 cm⁻¹.

EXAMPLE 6

6-keto-13,14-didehydro-PGF₁α and 6-Keto-13,14-didehydro-(15R)-PGF₁α.

A. There are first prepared the 5ξ-bromo-9-deoxy-6ξ,9-epoxy (15R and15S)-PGF₁α methyl ester compounds. A solution of the5ξ-bromo-9-deoxy-6ξ,9-epoxy-14-bromo-15-keto-PGF₁α, methyl ester(Example 3A, 0.93 g.) in 15 ml. of methanol is added to a solution ofsodium borohydride (0.46 g.) in 50 ml. of methanol at -50° C. Thereaction is continued at about -30° C. for 1.5 hr. The mixture iscarefully acidified with 5 ml. of acetic acid in 250 ml. of diethylether. The solution is washed with 0.2 M. potassium hydrogen sulfate, 5%sodium chloride, and 5% sodium bicarbonate, then dried and concentratedto yield the mixed C-15 epimers. The product is combined with 0.39 g.from another run and subjected to silica gel chromatography, elutingwith hexane-ethyl acetate (7:3). The respective fractions containing the15R and 15S products yield 0.34 g. of the 15R and 0.34 g. of the 15Sintermediate. The 15R compound has NMR peaks at 0.90, 1.1-2.75,2.75-3.30, 3.66, 3.78-4.8, 5.80 and 5.90 δ; and infrared peaks at 3350,1740, 1650, 1430, 1365, 1240, 1190, 1070, and 1050 cm⁻¹. The 15Scompound has NMR peaks at 0.89, 1.1-3.2, 3.2-4.8, 3.66, 5.78, and 5.83δ; and infrared peaks at 3350, 1740, 1650, 1430, 1365, 1240, 1190, 1070,and 1050 cm⁻¹.

B. A solution of the 15-S product from part A above (0.29 g.) in 5 ml.of dimethyl sulfoxide and 0.5 ml. of methanol is treated with potassiumtert-butoxide (0.3 g.) for 20 hr. On hydrolysis of the methyl ester with2 N. NaOH for 3 hr. followed by dilution with 5% sodium chloride,acidifying with 10% phosphoric acid, extraction with diethyl ether,washing with 5% sodium chloride, drying, and concentrating there isobtained 0.20 g. residue. The residue is subjected to silica gelchromatography, eluting with hexane-ethyl acetate (1:1 to 3:2), to yieldthe 15S title compound, 0.065 g., having the same properties as theproduct of Example 5.

Likewise, using the 15R intermediate of part A there is obtained thecorresponding 15R title compound having R_(f) 0.20 (TLC on silica gelplates in A-IX solvent).

Following the procedures of Example 6 Part B but substituting sodiummethoxide for potassium tert-butoxide there are also obtained the titlecompounds.

EXAMPLE 7

6-keto-13,14-didehydro-(15R)-PGE₁ (Formula VI)

A. Refer to Chart C. There is first prepared the formula-XIV14-bromo-(15R)-PGF₂α, methyl ester. Following the procedure of Example3-C above, the formula-XIII-15β compound, (15R)-5ξ,6ξ,14-tribromo-PGF₁α, methyl ester (1.52 g.) is treated with zinc dust andammonium chloride in methanol to yield the formula-XIV 15R compound,1.13 g., having R_(f) 0.40 (TLC on silver nitrate-treated silica gel inethyl acetate), NMR and infrared spectra very similar to those of the15S epimer of Example 3-C.

B. 5ξ-lodo-9-deoxy-6ξ,9-epoxy-14-bromo-(15R)-PGF₁α, methyl ester (XV).Following the procedure of Example 3-D, the formula-XIV14-bromo-(15R)-PGF₂α, methyl ester (0.98 g.) is iodinated to theformula-XV iodo compound. The product is chromatographed on silica gel,eluting with ethyl acetate (30%)-hexane to yield the desired compound,0.88 g., having NMR and infrared spectra very similar to those of the15S epimer of Example 3-D.

C. 5ξ-lodo-9-deoxy-6ξ, 9-epoxy-14-bromo-(15R)-PGF₁α, 11,15-bis(tetrahydropyran-2-yl ether), methyl ester (XVI). Following theprocedure of Example 3E, the formula-XV5ξ-iodo-9-deoxy-6ξ,9-epoxy-14-bromo-(15R)-PGF₁α, methyl ester (2.16 g.)is reacted with dihydropyran to form the formula-XVI bis(THP ether),3.24 g., having R_(f) 0.57 and 0.62 (TLC on silica gel in ethylacetate-cyclohexane (1:2) and having NMR and infrared spectra verysimilar to those of the 15S epimer of Example 3-E.

D. 6-Keto-13,14-didehydro-(15R)-PGF₁α, 11,15-bis(tetrahydropyran-2-ylether) (XVII). Following the procedure of Example 3-F, the formula-XVI5ξ-iodo-9-deoxy-6ξ,9-epoxy-14-bromo-(15R)-PGF₁α,11,15-bis(tetrahydropyran2-yl ether), methyl ester (3.27 g.) is reactedwith potassium t-butoxide in dimethyl sulfoxide-methanol, removing aless polar by-product by silica gel chromatography, to yield theproduct, 0.74 g., having R_(f) 0.51 (TLC on silica gel in a solventprepared by diluting the organic phase from ethyl acetate-aceticacid-cyclohexane-water (9:2:5:10) with half its volume of cyclohexane),and having NMR and infrared spectra very similr to those of the 15Sepimer of Example 3-F.

E. 6-Keto-13,14-didehydro-(15R)-PGE₁, 11,15-bis(tetrahydropyran-2-ylether) (V). Refer to Chart A. Following the procedure of Example 4, theformula-XVII (or IV) 6-keto-13,14-didehydro-(15R)-PGF₁α, 11,15-bis(tetrahydropyran-2-yl ether) (0.46 g.) is oxidized with Jonesreagent to the formula-V compound, 0.23 g., having R_(f) 0.55 (TLC onsilica gel in the solvent of section D above, having NMR peaks at 0.90,1.1-3.2, 3.2-4.65, 4.65-5.2 and 8.91 δ, and infrared absorption band at2600-3200, 2220, 1740, 1710, 1195, 1120, 1070, 1035, 995, 980, 965, and910 cm⁻¹.

F. 6-Keto-13,14-didehydro-(15R)-PGE₁ (VI). Following the procedure ofExample 4, the above bis(THP ether) (0.23 g) is hydrolyzed andchromatographed to yield the title compound, 0.10 g., m.p. 72° C. whencrystallized from diethyl ether-methylene chloride-hexane, having R_(f)0.36 (TLC on silica gel in the organic phase from ethyl acetate-aceticacid-cyclohexane-water (9:2:5:10)), having NMR peaks at 0.90, 1.1-2.0,2.0-3.2, 3.9-4.7, and 6.0-6.7 δ, and mass spectral peaks (TMSderivative) at 567.299, 564, 549, 511, 492, 477, 421, 402, 387, 367,201, and 111.

EXAMPLE 8

2-decarboxy-2-hydroxymethyl-6-keto-PGE₁, (Formula XXV: Q is ##STR128##R₂ is hydrogen, R₄ is n-pentyl, ##STR129## is ##STR130## X istrans-CH═CH--, and f is one).

I. Refer to Chart E. There is first prepared the formula-XXIII4,5-acetylenic PGF₁α type compound. The formula-XXII bis(THP ether)lactone (Corey et al., J. Am. Chem. Soc. 92, 397 (1970)) (6.5 g.) in 30ml. of tetrahydrofuran is reacted with4-trimethylsilyloxy-1-pentynyl-lithium (C.H. Lin, J. Org. Chem. 41, 4045(1976) (3.6 g.) at -70° to -60° C. for about 0.5 hr. The adduct isisolated and dissolved in 30 ml of isopropyl alcohol-water (4:1) andtreated with about 0.5 ml. of 10% aqueous sodium hydrogen sulfate. Themixture is stirred at about 25° C. for 0.5 hr., treated with about 10ml. of aqueous sodium bicarbonate, and concentrated to remove isopropylalcohol. The residue is extracted with diethyl ether and the organicphase is washed with water, aqueous sodium hydrogen sulfate, aqueoussodium bicarbonate, and brine, dried, and concentrated. The residue ischromatographed on silica gel eluting with ethyl acetate-hexane (1:5),to yield the formula-XXIII2-decarboxy-2-hydroxymethyl-4,4,5,5-tetradehydro-6-keto-PGF₁α,11,15-bis(tetrahydropyran-2-yl ether), 5.6 g. having NMR peaks at5.68-5.36, 4.8-4.5, and 4.5-3.18 δ, infrared absorption peaks at 3440,2210, 1675 and 975 cm⁻¹, and mass spectral lines (TMS derivative) at649.3986, 563, 557, 509, 479, 478, 463, and 85.

II. There is next prepared the formula-XXIV2-decarboxy-2-hydroxymethyl-4,4,5,5-tetradehydro-6-keto-PGE₁. Theproduct of 1 above (2.6 g.) is treated in 50 ml. of acetone with Jonesreagent (5.6 ml. of 2.67 M) in 30 ml. acetone added dropwise over 5 min.at -30° C. The reaction is quenched with aqueous sodium bisulfite andthe mixture concentrated to remove acetone. The residue is extractedwith ethyl acetate and the organic phase is washed with brine, dried,and concentrated. The resulting mixture is then methylated withdiazomethane to form the methyl ester of any carboxylic acid present.

The above mixture containing2-decarboxy-2-hydroxymethyl-4,5-tetradehydro-6-keto-PGE₁,11,15-bis(tetrahydropyran-2-yl ether) and methyl ester by-products ishydrolyzed in 20 ml. of acetic acid-tetrahydrofuran-water (3:1:1) at40°-45° C. for 3 hr. The mixture is concentrated and the residueextracted with ethyl acetate. The organic phase is washed with aqueoussodium bicarbonate and brine, dried, and concentrated. The residue ischromatographed on silica gel (HPLC), eluting with acetone(25-50%)-hexane to obtain the more polar formula-XXIV compound, 0.278g., having NMR peaks at 5.70-5.42, 4.32-3.80, and 3.23 δ, infraredabsorption bands at 3480, 2210, 1755, 1670, and 970 cm⁻¹, and a highresolution mass spectral peak (TMS derivative) at 566.3299.

III. Finally, the title compound is obtained by catalytic hydrogenationof the above compound. The formula-XXIV compound of II above (0.35 g.),together with 35 mg. of palladium on barium sulfate and 5 ml. ofpyridine is stirred under hydrogen at one atmosphere at about 25° C. for0.5 hr. The solids are removed by filtration and the filtrate isconcentrated. The residue is chromatographed ca 30-50 μ silica gel(HPLC), eluting with acetone-hexane (1:1) to yield the formula-XXV titlecompound, 0.178 g., having NMR peaks at 5.72-5.42, 4.34-3.78, and 3.60δ, infrared absorption bands at 3360, 1745, 1710, 1590, 1160, 1070.1015, and 970 cm⁻¹, and mass spectral lines (TMS derivative) at570.3563, 555, 552, 499, 480, 465, 426,409, 383, 375, 355, and 313.

Following the procedures of Example 8 and Chart E, but replacing theformula-XXII starting material with the appropriate lactone known in theart, there are obtained the following formula-XXV compounds

2-Decarboxy-2-hydroxymethyl-6-keto-16-phenyl-17,18,19,20-tetranor-PGE₁

2-decarboxy-2-hydroxymethyl-6-keto-(15S)-15-methyl-PGE₁,

2-decarboxy-2-hydroxymethyl-6-keto-13,14-dihydro-PGE₁,

2-decarboxy-2-hydroxymethyl-6-keto-13,14-didehydro-PGE₁.

Alternatively, the 13,14-dihydro- and 13,14-didehydro compounds areobtained by transformations of the above product of Example 8 or theformula-XXIV intermediate of Example 8 using methods known in the art.

EXAMPLE 9

6,15-diketo-PGE₁ (Formula XXXV)

I. Refer to Chart F. The formula-XXX 11,15-bis(tetrahydropyran-2-ylether) of 6-keto-PGF₁α, methyl ester is first prepared. A solution of6-keto-PGF₁α, methyl ester (Johnson et al., J. Am. Chem. Soc. 99, 4182(1977)) (0.3 g.) in 10 ml. of methylene chloride is treated with 2 ml.of dihydropyran and one ml. of a saturated solution of pyridinehydrochloride in methylene chloride and left standing at about 25° C.for several days. The mixture is washed with aqueous sodium bicarbonate,dried, and concentrated. The residue is chromatographed on silica gel,eluting with acetone (0-20%)-methylene chloride, to yield the bis(THPether), 0.23 g., having R_(f) 0.20 (TLC on silica gel in acetone(10%)-methylene chloride).

II. There is next prepared the formula-XXXII acid. The product above,combined with another lot of similar material (total 1.30 g.) is stirredwith 40 ml. of methanol and 10 ml. of 3 N sodium hydroxide at aout 25°C. for 3 hr. The mixture is cooled in an ice bath, saturated with sodiumchloride, acidified with potassium hydrogen sulfate and immediatelyextracted with ethyl acetate. The organic phase is washed with brine,dried, and concentrated. The acid has R_(f) 0.52 (TLC on silica gel inA-lX system).

III. There is next prepared the formula-XXXIV 15-oxo compound. The aboveproduct is immediately dissolved in 75 ml. of acetone, cooled to -15°C., and treated with 3 ml. of Jones reagent added slowly within 30 min.Stirring is continued for one hr., allowing the temperature to rise to-3° C.; then 0.5 ml. more Jones reagent is added, again at -10° C., andstirring continued for 45 min. The reaction is quenched with isopropylalcohol, dried, and concentrated to an oil, about 1.5 g., having R_(f)0.7 (TLC on silica gel in A-IX system).

IV. Finally, the title compound is obtained by hydrolysis. The aboveformula-XXXIV 6,15-diketo-PGE₁, 11,15-bis(tetrahydropyran-2-yl ether) istreated with 12 ml. of acetic acid and 5 ml. of water at 40° C. for 3hrs. Then the mixture is cooled, diluted with brine, and extracted withchloroform. The organic phase is washed with brine, dried, andconcentrated. The residue is chromatographed on 100 g. of silica gel,eluting with ethyl acetate (60-100%)-hexane, taking 50 ml. fractions andcombining fractions 13-20, to yield the formula-XXXV title compound,0.31 g., having R_(f) 0.36 (TLC on silica gel in A-lX system), NMR peaksat 7.37, 6.82, 4.2, 2.1-2.9, and 0.9 δ, and infrared absorption bands at3400-3200, 2660, 1745, 1715, 1675, 1630, 1290, 1245, 1160, 1095, 1075,975, 850, and 735 cm⁻¹.

EXAMPLE 10

6-keto-PGE₁, Amide (Formula I).

A solution of 6-keto-PGE₁ (Example 2, 0.17 g.) in 7 ml. of acetone istreated at -10° C. with 0.2 ml. of triethylamine and 0.2 ml. ofisobutylchloroformate. After 10 min. stirring the mixture is treatedwith 4 ml. of a saturated solution of ammonia in acetonitrile. After 15min. at -10° C. the cooling bath is removed and stirring continued for 5min. The mixture is then concentrated to one-half volume and dilutedwith water and ethyl acetate. The organic phase is separated, washedwith brine, dried, and concentrated. The oily residue is chromatographedon silica gel, eluting with acetone (40-100%)-methylene chloride toyield the title compound, 0.075 g. An analytical sample is obtained bycrystallizing from ethyl acetate-diethyl ether, a powder, m.p. 84°-6°C., having R_(f) 0.23 (TLC on silica gel in methanol-aceticacid-chloroform (10:10:80)) and infrared absorption bands at 3540, 3420,3200, 1745, 1710, 1655, 1620, 1295, 1245, 1160, 1110, 1075, 1025, and975 cm⁻¹.

Following the procedures of Example 10, but replacing the startingmaterial with (15S)-15-methyl-6-keto-PGE₁, there is obtained theformula-1 compound: (15S)-15-Methyl-6-keto-PGE₁, amide.

EXAMPLE 11

6-keto-PGE₁, Methylamide (Formula XL).

I. Refer to Chart C. There is first prepared the formula-XXXVII11,15-bis(tetrahydropyran-2-yl ether). A mixture of the formula-VII5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, methylamide (Preparation 8, 1.2 g.) in25 ml. methylene chloride, with 2 ml. of dihydropyran and 25 mg. ofp-toluenesulfonic acid monohydrate is stirred at about 25° C. for onehr. The mixture is then diluted with 75 ml. of methylene chloride,washed with saturated aqueous sodium bicarbonate and brine, dried, andconcentrated. The residue, an oil, is chromatographed on silica gel,eluting with acetone (5.40%)-methylene chloride to yield the bis(THPether) of the 5-iodo compound, mixed isomers, an oil, 1,6 g., havngR_(f) 0.10 and 0.03 (TLC on silica gel in acetone (10%)-methylenechloride).

II. There is next prepared the formula-XXXVIII 6-keto-PGF₁α,methylamide, 11,15-bis(tetrahydropyran-2-yl ether). A slution of theabove formula-XXXVII compound in 60 ml. of tetrahydrofuran is treatedwith silver carbonate (0.75 g.) and about 0.3 ml. of perchloric acid,with stirring at about 25° C. for 20 hr. The mixture is filtered,diluted with ethyl acetate, washed with brine, dried, and concentratedto an oil, 1.4 g. The residue is chromatographed on silica gel, elutingwith acetone (10-60%)-methylene chloride, to yield the formula-XXXVIIIcompound, 0.48 g., having R_(f) 0.26 (TLC on silica gel inacetone-methylene chloride (1:1)).

III. Next is prepared the formula-XXXIX 6-keto-PGE₁, methylamide,11,15-bis(tetrahydropyran-2-yl ether). A solution of the aboveformula-XXXVIII compound (0.48 g.) in 15 ml. of acetone is treated at-15° to -20° C. with one ml. of Jones reagent added dropwise and stirredfor 45 min. Thereafter one ml. of isopropyl alcohol is added, withstirring for about 30 min. Brine and ethyl acetate are added and theorganic phase is washed with brine, dried, and concentrated to an oil,0.42 g., consisting of the title compound as its bis(THP ether).

IV. Finally, the above formula-XXXIX bis (THP ether) (0.42 g.) istreated in 9 ml. of acetic acid-water-tetrahydrofuran (20:10:3) at 40°C. for 3.5 hr. The solution is diluted with 15 ml. of water andfreeze-dried. The residue is taken up in 10 ml. of methylene chlorideand chromatographed over silica gel, eluting with acetone(30-80%)-methylene chloride to yield the title compound, 0.11 g., havingR_(f) 0.42 (TLC on silica gel in acetone), mass spectral lines (TMSderivative) at 597.3738, 582, 579, 507, 489, and 417, and infraredabsorption bands at 3340, 1745, 1705, 1640, 1545, 1270, 1160, 1110,1075, 1015, and 975 cm⁻¹.

EXAMPLE 12

6-keto-PGE₁, n-Butylamide (Formula XL).

I. Refer to Chart G. There is first prepared the formula-XXXVIII6-keto-PGF₁α, n-butylamide, 11,15-bis(tetrahydropyran-2-yl ether). Asolution of 6-keto-PGF₁α, n-butylamide (Preparation 10, 1.47 g.) in 50ml. of chloroform is treated at about 25° C. with 8 ml. of dihydropyranand 5 ml. of methylene chloride saturated with pyridine hydrochloride.Additional amounts of reagents are added until the reaction is showncompleted by TLC. The mixture is then washed with cold aqueous saturatedsodium bicarbonate and brine, dried, and concentrated. The residue ischromatographed on silica gel, eluting with acetone-methylene chloride(1:2) to yield the formula-XXXVIII compound, 0.7 g., having R_(f) 0.41(TLC on silica gel in ethyl acetate).

II. Next is prepared the formula-XXXIX 6-keto-PGE₁, n-butylamide, 11,15-bis(tetrahydropyran-2-yl ether), using 0.7 g. of the aboveformula-XXXVIII compound and following the procedure of Example II-III,there is obtained 0.39 g. of product, having R_(f) 0.55 (TLC on silicagel in ethyl acetate) and a strong infrared absorption band at 1740cm⁻¹.

III. Finally, the title compound is obtained by hydrolyzing the productof II above (0.39 g.) in 2 ml. of glacial acetic acid and one ml. ofwater at 40° C. for 3 hr. The mixture is azeotroped with toluene,concentrating to a solid. The residue is chromatographed on silica gel,eluting with acetone-ethyl acetate (1:1) to yield the title compound,0.2 g. An analytical sample is obtained on recrystallization fromacetone-Skellysolve B, 0.15 g., having R_(f) 0.20 (TLC on silica gel inethyl acetate), and m.p. 78°-81° C.

EXAMPLE 13

6-keto-PGE.sub. 1, Benzylamide (Formula XL).

I. Refer to Chart G. There is first prepared the formula-XXXVII11,15-bis(tetrahydropyran-2-yl ether). Following the procedure ofExample 8-I, the 5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, benzylamide(Preparation 11, 2.0 g.) is reacted with dihydropyran. The product, anoil, is chromatographed over silica gel, eluting with acetone(5-25%)-methylene chloride, to yield the bis(THP ether), 2.4 g., havingR_(f) 0.73 (TLC on silica gel in acetonemethylene chloride (1:1)).

II. There is next prepared the formula-XXXVIII 6-keto-PGF₁, benzylamide,11,15-bis(tetrahydropyran-2-yl ether) using the above formula-XXXVIIcompound. There is first prepared (5Z)-9-deoxy-6,9α-epoxy-Δ⁵ -PGF₁,benzylamide, 11,15-bis(tetrahydropyran-2-yl)ether by treating theformula-XXXVII compound (2.4 g.) in 100 ml. of benzene with 4 ml. of DBNat 40°-45° C. for 22 hr. The mixture is cooled, diluted with 25 ml. ofbenzene, and washed with 25 ml. of ice water. The benzene solution isdried and concentrated. The residue, an oil, is essentially the enolether, (5Z)-9-deoxy-6,9α-epoxy-Δ⁵ -PGF₁, benzylamide,11,15-bis(tetrahydropyran-2-yl ether).

The above product is converted to the formula-XXXVIII 6-keto compound bytreating with 50 ml. of tetrahydrofuran-5% hydrochloric acid (9:1) atabout 25° C. for 15 min. The mixture is diluted with 50 ml. of brine andextracted with ethyl acetate. The organic phase is washed with brine,dried and concentrated to yield the formula-XXXVIII bis(THP ether), 2.0g., an oil.

III. Next is prepared the formula-XXXIX 6-keto-PGE₁, benzylamide,11,15-bis(tetrahydropyran-2-yl ether). The above formula-XXXVIII PGF₁compound, (1.0 g.) is oxidized in 25 ml. of acetone with Jones reagent(2 ml.) at -10° to -20° C., adding the reagent dropwise over 2 min. Themixture is stirred for 30 min. and the reaction is quenched with 2 ml.of isopropyl alcohol. The mixture is diluted with brine and extractedwith ethyl acetate. The organic phase is washed with brine, dried oversodium sulfate, and concentrated to the formula-XXXIX bis(THP ether),0.97 g.

IV. Finally, the title compound is obtained by hydrolyzing the productof III above (0.97 g.) in 20 ml. of acetic acid-water-tetrahydrofuran(20:10:3) at 40°-45° C. for 3.5 hr. The solution is diluted with 30 ml.of water and freeze-dried. The residue is chromatographed on Florisil ®,eluting with acetone (0-100%)-methylene chloride to yield the formula-XLtitle compound, 0.22 g. plus another 0.07 g. from rechromatographing amixture with less polar material. The product has R_(f) 0.24 inacetone-methylene chloride (1:1), and NMR peaks at 7.25, 6.5-6.8,5.4-5.7, 4.2-4.5, 3.5-4.2, 1.9-3.0, and 0.3-1.9 δ.

EXAMPLE 14

6-keto-PGE₁, Anilide (Formula XL)

I. Refer to Chart G. There is first prepared the formula-XXXVII11,15-bis(tetrahydropyran-2-yl ether). Following the procedure ofExample 11-I, the 5ξ-iodo-9-deoxy-6ξ,9α-epoxy-PGF₁, anilide (Preparation12, 1.8 g.) is reacted with dihydropyran. The product, 3.5 g., ischromatographed on silica gel, eluting with acetone (5-20%)-methylenechloride to yield the bis(THP ether), 2.3 g. having R_(f) 0.29 (TLC onsilica gel in acetone (10%)-methylene chloride).

II. There is next prepared the formula-XXXVII 6-keto-PGF₁α, anilide,11,15-bis(tetrahydropyran-2-yl ether) using the above formula-XXXVIIcompound and following the procedure of Example 11-II. The product, 1.98g., is chromatographed on silica gel eluting with acetone(10-70%)-methylene chloride to yield the product, 0.53 g., having R_(f)0.66 (TLC on silica gel in acetone-methylene chloride (1:1)).

III. Next is prepared the formula-XXXIX 6-keto-PGE₁, anilide,11,15-bis(tetrahydropyran-2-yl ether) using the above formula-XXXVIIIcompound and following the procedure of Example 11-III, to obtain 0.54g. of oil.

IV. Finally, the title compound is obtained by hydrolyzing the productof III above following the procedure of Example II-IV. The product ischromatographed on silica gel, eluting with acetone (10-60%)-methylenechloride to obtain the title compound, 0.18 g., having R_(f) 0.33 (TLCon silica gel in acetone-methylene chloride (1:1)), high resolution massspectral peak (TMS derivative) at 659.3837, and infrared absorptionpeaks at 3460, 3400, 3300, 1750, 1725, 1705, 1660, 1600, 1500, 1310,1290, 1260, 1155, 1100, 1065, 1030, 970, 755, and 690 cm⁻¹.

EXAMPLE 15

6-keto-PGE₁, p-Phenylphenacyl Ester (Formula VI).

Refer to Chart B. Following the procedures of Example 11, theformula-VII product of Preparation 4, 5ξ-iodo-9-deoxy-6,9-epoxy-PGF₁α,p-phenylphenacyl ester, is converted, first to its bis(THP ether), thento the formula-IV 6-keto-PGF₁α -type compound which is oxidized at theC-9 position to the formula-V compound which is finally hydrolyzed tothe formula-VI title compound.

Following the procedures of Example 15 and Chart B but replacing thestarting material with the corresponding p-phenylphenacyl ester made bymethods described herein or known in the art, there are obtained thefollowing formula-VI compounds:

(15S)-15-Methyl-6-keto-PGE₁, p-phenylphenacyl ester

16,16-Dimethyl-6-keto-PGE₁, p-phenylphenacyl ester.

EXAMPLE 16

6-keto-PGE₁, p-(p-Acetamidobenzamido)phenyl Ester (Formula VI)

Refer to Chart B. A solution of the formula-VII5ξ-iodo-9-deoxy-6,9-epoxy-PGF₁α free acid (Preparation 3) is convertedto the mixed anhydride with isobutylchloroformate in the presence oftriethylamine in acetone solution at about -10° C. Thereafter thesubstituted phenyl ester is obtained usingp-(p-acetamidobenzamido)phenol in pyridine at about 25° C.

Thereafter following the procedures of Example 11, the bis(THP ether) isformed and converted to the formula-IV 6-keto-PGF₁α -type compound,which is oxidized at the C-9 position and finally deblocked by mild acidhydrolysis to form the title compound of formula VI.

Following the procedures of Example 16 and Chart B, but replacing thatstarting material of formula VII with the appropriate 5-halo compoundand that phenol with the appropriate substituted phenol, there areprepared the following substituted phenyl esters within the scope offormula-VI:

6-keto-PGE₁, p-benzaldehyde semicarbazone ester

(15S)-15-Methyl-6-keto-PGE₁, p-(p-acetamidobenzamido)phenyl ester

16,16-Dimethyl-6-keto-PGE₁, p-(p-acetamidobenzamido)phenyl ester

(15S)-15-Methyl-6-keto-PGE₁, p-benzaldehyde semicarbazone ester

16,16-Dimethyl-6-keto-PGE₁, p-benzaldehyde semicarbazone ester.

I clam:
 1. A compound of the formula ##STR131## wherein D₁ is (1) --(CH₂)_(d) --C(R₂)₂ --or(2) --CH₂ --O--CH₂ --Y-- wherein d is zero to 5, R₂is hydrogen, methyl, or fluoro, being the same or different with theproviso that one R₂ is not methyl when the other is fluoro, and Y is avalence bond, --CH₂ -- or --(CH₂)₂ --, --CH₂ -- or --(CH₂)₂, ##STR132##wherein R₇ is ##STR133## wherein R₂₀ is (a) hydrogen, (b) alkyl of oneto 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms,inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl,(f) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4carbon atoms, inclusive, ##STR134## wherein R₁₀ is phenyl,p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or2-naphthyl, and wherein R₁₁ is hydrogen or benzoyl, wherein C_(g)H₂.sbsp.g is alkylene of one to 9 carbon atoms, inclusive, with one to 5carbon atoms, inclusive in the chain between --CR₅ R₆ -- and terminalmethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatone of R₅ and R₆ is fluoro only when the other is hydrogen orfluorowherein R₂₉ is bromo or chloro, and ˜ indicates attachment inalpha or beta configuration.
 2. 5ξ,6ξ,14-Tribromo-(15R)-PGF₁α, methylester, a compound according to claim
 1. 3. 5ξ,6ξ,14-Tribromo-PGF₁α,methyl ester, a compound according to claim 1.